2,5-disubstituted arylsulfonamide CCR3 antagonists

ABSTRACT

Provided herein are 2,5-disubstituted arylsulfonamides that are useful for modulating CCR3 activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CCR3-mediated disorder, disease, or condition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/764,900, filed Apr. 21, 2010, and claims priority to U.S. ProvisionalApplication No. 61/171,775, filed Apr. 22, 2009, the disclosure of eachof which is incorporated herein by reference in its entirety.

FIELD

Provided herein are 2,5-disubstituted arylsulfonamides that are usefulfor modulating CCR3 activity, and pharmaceutical compositions thereof.Also provided herein are methods of their use for treating, preventing,or ameliorating one or more symptoms of a CCR3-mediated disorder,disease, or condition.

BACKGROUND

CC chemokine receptor 3 (CCR3) is a seven-transmembrane Gprotein-coupled receptor, which binds to a variety of C—C chemokines,including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4(CCL13), and RANTES (CCL5). CCR3 is known to be a major chemokinereceptor expressed on allergic inflammatory cells, includingeosinophils, basophils, mast cells, and T helper 2-type CD4⁺ cells(Combadiere et al. J. Biol. Chem. 1995, 270, 16491-16494; Post et al.,J. Immunol. 1995, 155, 5299-5305). Eosinophils have been implicated inthe pathogenesis of a number of allergic diseases, such as bronchialasthma (Durham and Kay, Clin. Allergy 1985, 15, 411-418; Kroegel et al,J. Allergy Clin. Immunol 1994, 93, 725-734), allergic rhinitis (Durham,Clin. Exp. Allergy 1998, 28 Suppl. 2, 11-16), atopic dermatitis (Leung,J. Allergy Clin. Immunol. 1999, 104, S99-108), and eosinophilicgastroenteritis (Bischoff et al., Am. J. Gastro. 1999, 94, 3521-3529).It has been demonstrated that activated eosinophils release major basicprotein (MBP), which blocks inhibitory M2 muscarinic receptors (M2Rs) onnerves, increasing acetylcholine release, and potentiating vagallymediated bronchoconstriction (Evans et al., J. Clin. Invest. 1997, 100,2254-2262).

Numerous reports indicate that CCR3 plays important roles in allergicconditions. For example, it has been reported that, in both atopic andnonatopic asthma patients, there are increases in both mRNA and proteinlevels of CCR3 and its ligands, eotaxin, eotaxin-2. RANTES, and MCP-4(Ying et al., J. Immunol. 1999, 99, 6321-6329). It has also beendemonstrated that CCR3 gene deletion impairs eosinophil recruitment inan acute model of experimental asthma (Humbles et al., Proc. Natl. Acad.Sci. USA 2002, 99, 1479-1484; Ma et al., J. Clin. Invest. 2002, 109,621-628; Pope et al., J. Immunol. 2005, 175, 5341-5350; Fulkerson etal., Proc. Natl. Acad. Sci. USA 2006, 103, 16418-16423). Furthermore,studies have shown that CCR3 antagonists, such as anti-CCR3 monoclonalantibodies, block binding of CCR3-ligands to either CCR3 transfectantsor eosinophils, thus blocking chemotaxis of eosinophils induced by C—Cchemokines, such as eotaxin, RANTES, or MCP-3 (Heath et al., J. Clin.Invest. 1997, 99, 178-184; Grimaldi et al., J. Leukocyte Biol. 1999, 65,846-853; Justice et al., Am. J. Physiol. 2003, 284, L168-L178).Therefore, CCR3 antagonists are potentially useful for the treatment ofinflammatory diseases, such as allergic rhinitis and allergic asthma. Inaddition, CCR3 antagonists are also potentially useful blockinginfection of CCR3 expressing cells by some microorganisms, such as HIV,as CCR3 is known to be an entry co-receptor for some microorganisms.

SUMMARY OF THE DISCLOSURE

Provided herein is a 2,5-disubstituted arylsulfonamide of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;wherein:

R¹ and R² are each independently (a) halo, cyano, nitro, hydroxyl, orguanidine; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein thealkyl, alkoxy, and alkylthio are each independently and optionallysubstituted with one, two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, benzyl, phenoxy, benzoxy, or heterocyclyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R³ is (a) hydrogen, halo, cyano, nitro, or hydroxyl; (b) C₁₋₆ alkyl,C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthioare each independently and optionally substituted with one, two, orthree halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, or tetrazolyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or S(O)₂NR^(1b)R^(1c);

R⁴ is

R⁵ is (a) halo, cyano, nitro, hydroxyl, oxo, or guanidine; (b) C₁₋₆alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, andalkylthio are each independently and optionally substituted with one,two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, benzyl,phenoxy, benzoxy, or heterocyclyl; or (d) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or—S(O)₂NR^(1b)R^(1c);

X is O or S:

Y is —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 4;

r is an integer from 1 to 6; and

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently (a) hydrogen,phenyl, or benzyl; (b) C₃₋₇ cycloalkyl, heteroaryl, or heterocyclyl,each optionally substituted; or (c) C₁₋₆ alkyl, optionally substitutedwith one, two, or three substituents, each independently selected fromhalo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, andC₃₋₇ heterocyclylcarbamoyl; or

each pair of R^(1b) and R^(1c) together with the N atom to which theyare attached independently form heteroaryl or heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; in combination with one or more pharmaceuticallyacceptable carriers.

Further provided herein is a method for modulating CCR3 activity,comprising contacting a CCR3 with a therapeutically effective amount ofa compound disclosed herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

Additionally provided herein is a method for treating, preventing, orameliorating one or more symptoms of a CCR3-mediated disorder, disease,or condition in a subject, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, e.g., acompound of Formula I, an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, or a mixture of two ormore tautomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs. In the eventthat there is a plurality of definitions for a term used herein, thosein this section prevail unless stated otherwise.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer of a compound describedherein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl may optionally be substituted asdescribed herein. In certain embodiments, the alkyl is a linearsaturated monovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms). For example, C₁₋₆ alkyl refers to alinear saturated monovalent hydrocarbon radical of 1 to 6 carbon atomsor a branched saturated monovalent hydrocarbon radical of 3 to 6 carbonatoms.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon double bond(s). The alkenyl maybe optionally substituted as described herein. The term “alkenyl” alsoembraces radicals having “cis” and “trans” configurations, oralternatively, “Z” and “E” configurations, as appreciated by those ofordinary skill in the art. As used herein, the term “alkenyl”encompasses both linear and branched alkenyl, unless otherwisespecified. For example, C₂₋₆ alkenyl refers to a linear unsaturatedmonovalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. Incertain embodiments, the alkenyl is a linear monovalent hydrocarbonradical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radical of 3to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. Examples of alkenyl groups include, but are not limited to,ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon triple bond(s). The alkynyl maybe optionally substituted as described herein. The term “alkynyl” alsoencompasses both linear and branched alkynyl, unless otherwisespecified. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₇₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethynyl (—C≡CH) and propargyl(—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to a linear unsaturatedmonovalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,which may be optionally substituted as described herein. In oneembodiment, cycloalkyl groups may be saturated, and/or bridged, and/ornon-bridged, and/or fused bicyclic groups. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10(C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “aryl” refers to a monovalent monocyclic aromatic group and/ormonovalent multicyclic aromatic group that contain at least one aromaticcarbon ring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀),from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl,fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, andterphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, whereone of the rings is aromatic and the others of which may be saturated,partially unsaturated, or aromatic, for example, dihydronaphthyl,indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certainembodiments, aryl may be optionally substituted as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupand/or multicyclic aromatic group that contain at least one aromaticring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, and N in the ring.Heteroaryl groups are bonded to the rest of the molecule through thearomatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, and/or one to four N atoms, provided that thetotal number of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments,heteroaryl may also be optionally substituted as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system and/or multicyclic ring system thatcontains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, or N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. Heterocyclyl groups are bonded to the rest of the moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay include a fused or bridged ring system, and in which the nitrogen orsulfur atoms may be optionally oxidized, the nitrogen atoms may beoptionally quaternized, and some rings may be partially or fullysaturated, or aromatic. The heterocyclyl may be attached to the mainstructure at any heteroatom or carbon atom which results in the creationof a stable compound. Examples of such heterocyclic radicals include,but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl,benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, p-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also beoptionally substituted as described herein.

The term “alkoxy” refers to an —OR radical, wherein R is, for example,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,each as defined herein. Examples of alkoxy groups include, but are notlimited to, methoxy, ethoxy, propoxy, n-propoxy, 2-propoxy, n-butoxy,isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzoxy, and2-naphthyloxy. In certain embodiments, alkoxy may be optionallysubstituted as described herein. In certain embodiments, alkoxy is C₁₋₆alkyl-oxy.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group, suchas an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, or alkoxy group, may be substituted with one or moresubstituents independently selected from, e.g., (a) alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, each optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q; and (b) halo, cyano (—CN), nitro (—NO₂),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, eachoptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q; or (iii) R^(b) and R^(c) together withthe N atom to which they are attached form heterocyclyl, optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q. As used herein, all groups that can be substitutedare “optionally substituted,” unless otherwise specified.

In one embodiment, each Q is independently selected from the groupconsisting of (a) cyano, halo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, andheterocyclyl; and —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(e)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g);wherein each R^(e), R^(f), R^(g), and R^(h) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g)together with the N atom to which they are attached form heterocyclyl.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof one enantiomer and about 5% or less of the other enantiomer based onthe total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “solvate” refers to a compound provided herein or a saltthereof, which further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate.

The term “naturally occurring” or “native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, hostcells, and the like, refers to materials which are found in nature andare not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “CCR3” refers to CC chemokine receptor 3 or a variant thereof,which is capable of mediating a cellular response to a variety ofchemokines, including, but not limited to, eotaxin (CCL11), eotaxin-3(CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). CCR3 variantsinclude proteins substantially homologous to a native CCR3, i.e.,proteins having one or more naturally or non-naturally occurring aminoacid deletions, insertions or substitutions (e.g., CCR3 derivatives,homologs and fragments), as compared to the amino acid sequence of anative CCR3. The amino acid sequence of a CCR3 variant is at least about80% identical, at least about 90% identical, or at least about 95%identical to a native CCR3.

The term “CCR3 antagonist” refers to a compound that, e.g., partially ortotally blocks, decreases, prevents, inhibits, or downregulates CCR3activity. The term “CCR3 antagonist” also refers to a compound thatbinds to, delays the activation of, inactivates, or desensitizes a CCR3receptor. A CCR3 antagonist may act by interfering with the interactionof a CCR3 receptor and its chemokine ligand, including, but not limitedto, eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13),and/or RANTES (CCL5).

The terms “CCR3-mediated disorder or disease” and “a condition, disorderor disease mediated by CCR3” refer to a condition, disorder, or diseasecharacterized by inappropriate, e.g., less than or greater than normal,CCR3 activity. Inappropriate CCR3 functional activity might arise as theresult of CCR3 expression in cells which normally do not express CCR3,increased CCR3 expression or degree of intracellular activation, leadingto, e.g., inflammatory and immune-related disorders or diseases; ordecreased CCR3 expression. A CCR3-mediated condition, disorder ordisease may be completely or partially mediated by inappropriate CCR3activity. In particular, a CCR3-mediated condition, disorder or diseaseis one in which modulation of a CCR3 receptor results in some effect onthe underlying condition or disorder, e.g., a CCR3 antagonist or agonistresults in some improvement in at least some of patients being treated.

Compounds

Provided herein are 2,5-disubstituted arylsulfonamides which are usefulfor modulating CCR3 activity. Also provided herein are pharmaceuticalcompositions which comprise the compounds and methods of use of thecompounds and compositions for the treatment of a CCR3-mediateddisorder, disease, or condition.

In one embodiment, provided herein is a 2,5-disubstitutedarylsulfonamide of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;wherein:

R¹ and R² are each independently (a) halo, cyano, nitro, hydroxyl, orguanidine; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein thealkyl, alkoxy, and alkylthio are each independently and optionallysubstituted with one, two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, benzyl, phenoxy, benzoxy, or heterocyclyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R³ is (a) hydrogen, halo, cyano, nitro, or hydroxyl; (b) C₁₋₆ alkyl,C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthioare each independently and optionally substituted with one, two, orthree halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, or tetrazolyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁴ is

R⁵ is (a) halo, cyano, nitro, hydroxyl, oxo, or guanidine; (b) C₁₋₆alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, andalkylthio are each independently and optionally substituted with one,two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, benzyl,phenoxy, benzoxy, or heterocyclyl; or (d) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or—S(O)₂NR^(1b)R^(1c);

X is O or S;

Y is —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 4;

r is an integer from 1 to 6; and

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently (a) hydrogen,phenyl, or benzyl; (b) C₃₋₇ cycloalkyl, heteroaryl, or heterocyclyl,each optionally substituted; or (c) C₁₋₆ alkyl, optionally substitutedwith one, two, or three substituents, each independently selected fromhalo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, andC₃₋₇ heterocyclylcarbamoyl; or

each pair of R^(1b) and R^(1c) together with the N atom to which theyare attached independently form heteroaryl or heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In one embodiment, in Formula I,

R¹ and R² are each independently (a) halo, cyano, nitro, hydroxyl, orguanidine; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein thealkyl, alkoxy, and alkylthio are each independently and optionallysubstituted with one, two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, benzyl, phenoxy, benzoxy, or heterocyclyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)₂R^(1a), or —S(O)₂NR^(1b)R^(1c);

R³ is (a) hydrogen, halo, cyano, nitro, or hydroxyl; (b) C₁₋₆ alkyl,C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthioare each independently and optionally substituted with one, two, orthree halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, or tetrazolyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), or —NR^(1a)C(O)OR^(1d);

R⁴ is

R⁵ is (a) halo, cyano, nitro, hydroxyl, oxo, or guanidine; (b) C₁₋₆alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, andalkylthio are each independently and optionally substituted with one,two, or three halo; (c) alkenyl. C₂₋₆ alkynyl, phenyl, benzyl, phenoxy,benzoxy, or heterocyclyl; or (d) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)NR^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)S(O)₂R^(1d),—S(O)₂R^(1a), or —S(O)₂NR^(1b)R^(1c);

X is O or S;

Y is —O—, —S—, —S(O)—, —S(O)₂—, N(R^(1a))—, C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 4;

r is an integer from 1 to 6; and

each R^(1a) and R^(1d) is independently (a) hydrogen, phenyl, or benzyl;(b) C₃₋₇ cycloalkyl, heteroaryl, or heterocyclyl, each optionallysubstituted; or (c) C₁₋₆ alkyl, optionally substituted with one, two, orthree substituents, each independently selected from halo, hydroxyl,carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; and

each R^(1b) and R^(1c) is independently (a) hydrogen or phenyl; or (b)C₁₋₆ alkyl, optionally substituted with one, two, or three substituents,each independently selected from halo, hydroxyl, carboxy, alkoxy,carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, alkyl)carbamoyl, C₃₋₇cycloalkylcarbamoyl, and C₃₋₇ heterocyclylcarbamoyl; or

each pair of R^(1b) and R^(1c) together with the N atom to which theyare attached independently form heteroaryl or heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In another embodiment, in Formula I,

R¹ and R² are each independently halo or C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo;

R³ is cyano or nitro;

R⁴ is

R⁵ is C₁₋₆ alkyl, optionally substituted with one, two, or three halo;

X is O or S;

Y is —O—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, orC(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) and R^(1d) is independently (a) hydrogen; (b) C₃₋₇cycloalkyl, heteroaryl, or heterocyclyl, each optionally substituted; or(c) C₁₋₆ alkyl, optionally substituted with one, two, or threesubstituents, each independently selected from halo, hydroxyl, carboxy,alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; and

each R^(1b) and R^(1c) is independently C₁₋₆ alkyl, optionallysubstituted with one, two, or three substituents, each independentlyselected from halo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl,C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl,and C₃₋₇ heterocyclylcarbamoyl; or

each pair of R^(1b) and R^(1c) together with the N atom to which theyare attached independently form heterocyclyl; and

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro, and p is 0; then R^(1a) is not hydrogen.

In yet another embodiment, in Formula I,

R¹ and R² are each independently halo or C₁₋₆ alkyl;

R³ is cyano or nitro;

R⁴ is

R⁵ is C₁₋₆ alkyl;

X is O or S;

Y is —O—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) and R^(1d) is independently hydrogen, C₃₋₇ cycloalkyl,heterocyclyl, or C₁₋₆ alkyl; and

each R^(1b) and R^(1c) is independently C₁₋₆ alkyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form heterocyclyl; and

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are I; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In yet another embodiment, in Formula I,

R¹ and R² are each independently fluoro, chloro, methyl, ethyl, propyl(e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, 2-butyl,isobutyl, or t-butyl);

R³ is cyano or nitro;

R⁴ is

R⁵ is methyl;

X is O or S;

Y is —O—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) is hydrogen, methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl),cyclopentyl, or 3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl; and

R^(1d) is hydrogen;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In still another embodiment, in Formula I,

R¹ and R² are each independently fluoro, chloro, or methyl;

R³ is cyano or nitro;

R⁴ is

R⁵ is methyl;

X is O or S;

Y is —O—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) is hydrogen, methyl, isopropyl, 2-pentyl, 3-pentyl,cyclopentyl, or5-butyl-7-chloro-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl;

R^(1d) is hydrogen; with the proviso that when X is O; Y is —N(R^(1a))—;m and n are 1; R¹ and R² are each independently chloro, nitro, methyl,or isopropyl; R³ is nitro; and p is 0; then R^(1a) is not hydrogen.

In one embodiment, in Formula I,

R¹ and R² are each independently halo or C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo;

R³ is cyano or nitro;

R⁴ is

R⁵ is oxo; C₁₋₆ alkyl, optionally substituted with one, two, or threehalo; or —C(O)OR^(1a);

X is O or S;

Y is —O—, —S—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) and R^(1d) is independently (a) hydrogen; (b) C₃₋₇cycloalkyl, heteroaryl, or heterocyclyl, each optionally substituted; or(c) C₁₋₆ alkyl, optionally substituted with one, two, or threesubstituents, each independently selected from halo, hydroxyl, carboxy,alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; and

each R^(1b) and R^(1c) is independently C₁₋₆ alkyl, optionallysubstituted with one, two, or three substituents, each independentlyselected from halo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl,C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl,and C₃₋₇ heterocyclylcarbamoyl; or

each pair of R^(1b) and R^(1c) together with the N atom to which theyare attached independently form heterocyclyl; and

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro, and p is 0; then R^(1a) is not hydrogen.

In another embodiment, in Formula I,

R¹ and R² are each independently halo or C₁₋₆ alkyl;

R³ is cyano or nitro;

R⁴ is

R⁵ is oxo, C₁₋₆ alkyl, or C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl;

X is O or S;

Y is —O—, —S—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) and R^(1d) is independently hydrogen, C₃₋₇ cycloalkyl,heterocyclyl, or C₁₋₆ alkyl; and

each R^(1b) and R^(1c) is independently C₁₋₆ alkyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form heterocyclyl; and

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In yet another embodiment, in Formula I,

R¹ and R² are each independently fluoro, chloro, methyl, ethyl, propyl(e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, 2-butyl,isobutyl, or t-butyl);

R³ is cyano or nitro;

R⁴ is

R⁵ is methyl, oxo, or methoxycarbonyl;

X is O or S;

Y is —O—, —S—, —S(O)₂—, —C(R^(1a))(R^(1d))—, orC(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) is hydrogen, methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl),cyclopentyl, or 3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl; and

R^(1d) is hydrogen;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In still another embodiment, in Formula I,

R¹ and R² are each independently fluoro, chloro, or methyl;

R³ is cyano or nitro;

R⁴ is

R⁵ is methyl, oxo, or methoxycarbonyl;

X is O or S;

Y is —O—, —S—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

r is 2;

each R^(1a) is hydrogen, methyl, ethyl, isopropyl, 2-pentyl, 3-pentyl,cyclopentyl, cyclohexyl, or5-butyl-7-chloro-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl;

R^(1d) is hydrogen;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In another embodiment, the arylsulfonamide of Formula I has thestructure of Formula II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; wherein R¹, R², R³, R⁵, X, Y, n, and p are each asdefined herein.

In one embodiment, in Formula II,

R¹ and R² are each independently (a) halo, cyano, nitro, hydroxyl, orguanidine; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein thealkyl, alkoxy, and alkylthio are each independently and optionallysubstituted with one, two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, benzyl, phenoxy, benzoxy, or heterocyclyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)₂R^(1a), or S(O)₂NR^(1b)R^(1c);

R³ is (a) hydrogen, halo, cyano, nitro, or hydroxyl; (b) C₁₋₆ alkyl,C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthioare each independently and optionally substituted with one, two, orthree halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, or tetrazolyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c),NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), or —NR^(1a)C(O)OR^(1d);

R⁵ is (a) halo, cyano, nitro, hydroxyl, oxo, or guanidine; (b) C₁₋₆alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, andalkylthio are each independently and optionally substituted with one,two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, benzyl,phenoxy, benzoxy, or heterocyclyl; or (d) C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)S(O)₂R^(1d),—S(O)₂R^(1a), or S(O)₂NR^(1b)R^(1c);

X is O or S;

Y is —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(1a))—, C(R^(1a))(R^(1d))—, or—C(R^(1d))(NR^(1b)R^(1c))—;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 4;

each R^(1a) and R^(1d) is independently (a) hydrogen, phenyl, or benzyl;(b) C₃₋₇ cycloalkyl, heteroaryl, or heterocyclyl, each optionallysubstituted; or (c) C₁₋₆ alkyl, optionally substituted with one, two, orthree substituents, each independently selected from halo, hydroxyl,carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; and

each R^(1b) and R^(1c) is independently (a) hydrogen or phenyl; or (b)C₁₋₆ alkyl, optionally substituted with one, two, or three substituents,each independently selected from halo, hydroxyl, carboxy, alkoxy,carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl,C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇ heterocyclylcarbamoyl; or

each pair of R^(1b) and R^(1c) together with the N atom to which theyare attached independently form heteroaryl or heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; then R^(1a) is not hydrogen.

In another embodiment, in Formula II,

R¹ and R² are each independently halo or C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo;

R³ is cyano or nitro;

R⁵ is C₁₋₆ alkyl, optionally substituted with one, two, or three halo;

X is O or S;

Y is —O—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, orC(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

each R^(1a) and R^(1d) is independently (a) hydrogen; (b) C₃₋₇cycloalkyl, heteroaryl, or heterocyclyl, each optionally substituted; or(c) C₁₋₆ alkyl, optionally substituted with one, two, or threesubstituents, each independently selected from halo, hydroxyl, carboxy,alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, alkyl)carbamoyl,C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇ heterocyclylcarbamoyl; and

R^(1b) and R^(1c) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, or three substituents, each independentlyselected from halo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl,C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl,and C₃₋₇ heterocyclylcarbamoyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In yet another embodiment, in Formula II,

R¹ and R² are each independently halo or C₁₋₆ alkyl;

R³ is cyano or nitro;

R⁵ is C₁₋₆ alkyl;

X is O or S;

Y is —O—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

each R^(1a) and R^(1d) is independently hydrogen, C₃₋₇ cycloalkyl,heterocyclyl, or C₁₋₆ alkyl; and

R^(1b) and R^(1c) are each independently C₁₋₆ alkyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In yet another embodiment, in Formula II,

R¹ and R² are each independently fluoro, chloro, or methyl;

R³ is cyano or nitro;

R⁵ is methyl;

X is O or S;

Y is —O—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1d))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, or 2;

each R^(1a) is hydrogen, methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl),cyclopentyl, or 3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl; and

R^(1d) is hydrogen;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In still another embodiment, in Formula II,

R¹ and R² are each independently fluoro, chloro, or methyl;

R³ is cyano or nitro;

R⁵ is methyl;

X is O or S;

Y is —O—, —N(R^(1a))—, C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

each R^(1a) is hydrogen, methyl, isopropyl, 2-pentyl, 3-pentyl,cyclopentyl, or5-butyl-7-chloro-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl;

R^(1d) is hydrogen;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In one embodiment, in Formula II,

R¹ and R² are each independently halo or C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo;

R³ is cyano or nitro;

R⁵ is oxo; C₁₋₆ alkyl, optionally substituted with one, two, or threehalo; or —C(O)OR^(1a);

X is O or S;

Y is —O—, —S—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

each R^(1a) and R^(1d) is independently (a) hydrogen; (b) C₃₋₇cycloalkyl, heteroaryl, or heterocyclyl, each optionally substituted; or(c) C₁₋₆ alkyl, optionally substituted with one, two, or threesubstituents, each independently selected from halo, hydroxyl, carboxy,alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; and

R^(1b) and R^(1c) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, or three substituents, each independentlyselected from halo, hydroxyl, carboxy, alkoxy, carbamoyl. C₆₋₁₄ aryl,C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl,and C₃₋₇ heterocyclylcarbamoyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In another embodiment, in Formula II,

R¹ and R² are each independently halo or C₁₋₆ alkyl;

R³ is cyano or nitro;

R⁵ is oxo, C₁₋₆ alkyl, or —C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl;

X is O or S;

Y is —O—, —S—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

each R^(1a) and R^(1d) is independently hydrogen, C₃₋₇ cycloalkyl,heterocyclyl, or C₁₋₆ alkyl; and

R^(1b) and R^(1c) are each independently C₁₋₆ alkyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In yet another embodiment, in Formula II,

R¹ and R² are each independently fluoro, chloro, or methyl;

R³ is cyano or nitro;

R⁵ is methyl, oxo, or methoxycarbonyl;

X is O or S;

Y is —O—, —S—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

each R^(1a) is hydrogen, methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g.,n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl),cyclopentyl, or 3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl; and

R^(1d) is hydrogen;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In still another embodiment, in Formula II,

R¹ and R² are each independently fluoro, chloro, or methyl;

R³ is cyano or nitro;

R⁵ is methyl, oxo, or methoxycarbonyl;

X is O or S;

Y is —O—, —S—, —S(O)₂—, —N(R^(1a))—, —C(R^(1a))(R^(1d))—, or—C(R^(1a))(NR^(1b)R^(1c))—;

m is 1;

n is 1 or 2;

p is 0, 1, or 2;

each R^(1a) is hydrogen, methyl, isopropyl, 2-pentyl, 3-pentyl,cyclopentyl, or5-butyl-7-chloro-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl;

each R^(1b) and R^(1c) is independently methyl or ethyl; or each pair ofR^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl;

R^(1d) is hydrogen;

with the proviso that when X is O; Y is —N(R^(1a))—; m and n are 1; R¹and R² are each independently chloro, nitro, methyl, or isopropyl; R³ isnitro; and p is 0; R^(1a) is not hydrogen.

In yet another embodiment, the arylsulfonamide of Formula I has thestructure of Formula III:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; wherein R¹, R², R³, R^(1a), R^(1b), R^(1c), X, and rare each as defined herein.

In one embodiment, in Formula III,

R¹ and R² are each independently (a) halo, cyano, nitro, hydroxyl, orguanidine; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein thealkyl, alkoxy, and alkylthio are each independently and optionallysubstituted with one, two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, benzyl, phenoxy, benzoxy, or heterocyclyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)₂R^(1a), or —S(O)₂NR^(1b)R^(1c);

R³ is (a) hydrogen, halo, cyano, nitro, or hydroxyl; (b) C₁₋₆ alkyl,C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthioare each independently and optionally substituted with one, two, orthree halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, or tetrazolyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), or —NR^(1a)C(O)OR^(1d);

X is O or S;

r is an integer from 1 to 6;

each R^(1a) and R^(1d) is independently (a) hydrogen, phenyl, or benzyl;(b) C₃₋₇ cycloalkyl; or (c) C₁₋₆ alkyl, optionally substituted with one,two, or three substituents, each independently selected from halo,hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl,di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; and

each R^(1b) and R^(1c) is independently (a) hydrogen or phenyl; or (b)C₁₋₆ alkyl, optionally substituted with one, two, or three substituents,each independently selected from halo, hydroxyl, carboxy, alkoxy,carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl,C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇ heterocyclylcarbamoyl; or

each pair of R^(1b) and R^(1c) together with the N atom to which theyare attached independently form heteroaryl or heterocyclyl.

In another embodiment, in Formula III,

R¹ and R² are each independently halo or C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo;

R³ is cyano or nitro;

X is O or S;

r is 2;

R^(1a) is (a) hydrogen; or (b) C₁₋₆ alkyl, optionally substituted withone, two, or three substituents, each independently selected from halo,hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl,di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; and

R^(1b) and R^(1c) are each independently C₁₋₆ alkyl, optionallysubstituted with one, two, or three substituents, each independentlyselected from halo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl,C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl,and C₃₋₇ heterocyclylcarbamoyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In yet another embodiment, in Formula III,

R¹ and R² are each independently halo or C₁₋₆ alkyl;

R³ is cyano or nitro;

X is O or S;

r is 2;

R^(1a) is hydrogen; and

R^(1b) and R^(1c) are each independently C₁₋₆ alkyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl.

In still another embodiment, in Formula III,

R¹ and R² are each independently fluoro or methyl;

R³ is cyano;

X is O or S;

r is 2;

R^(1a) is hydrogen; and

R^(1b) and R^(1c) are ethyl; or

R^(1b) and R^(1c) together with the N atom to which they are attachedindependently form pyrrolidinyl or piperidinyl.

The groups, R¹, R², R³, R⁴, R⁵, R^(1a), R^(1b), R^(1c), R^(1d), X, Y, m,n, p, and r in Formula I, II, or III are further defined in theembodiments described herein. All combinations of the embodimentsprovided herein for such groups are within the scope of this disclosure.

In certain embodiments, R¹ is halo, cyano, nitro, hydroxyl, orguanidine. In certain embodiments, R¹ is halo. In certain embodiments,R¹ is fluoro or chloro. In certain embodiments, R¹ is C₁₋₆ alkyl, C₁₋₆alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthio areeach independently and optionally substituted with one, two, or threehalo. In certain embodiments, R¹ is C₁₋₆ alkyl, optionally substitutedwith one, two, or three halo. In certain embodiments. R¹ is methyl,ethyl, propyl (e.g., n-propyl and isopropyl), butyl (n-butyl, 2-butyl,isobutyl, or t-butyl), or pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R¹ is methyl. In certainembodiments, R¹ is C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, benzyl, phenoxy,benzoxy, or heterocyclyl. In certain embodiments. R¹ is —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein. In certain embodiments,R¹ is —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—OC(O)NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)S(O)₂R^(1d), —S(O)₂R^(1a), or—S(O)₂NR^(1b)R^(1c); wherein R^(1d), R^(1b), R^(1c), and R^(1d) are eachas defined herein.

In certain embodiments, R² is halo, cyano, nitro, hydroxyl, orguanidine. In certain embodiments, R² is halo. In certain embodiments,R² is fluoro or chloro. In certain embodiments, R² is C₁₋₆ alkyl, C₁₋₆alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthio areeach independently and optionally substituted with one, two, or threehalo. In certain embodiments, R² is C₁₋₆ alkyl, optionally substitutedwith one, two, or three halo. In certain embodiments, R² is methyl,ethyl, propyl (e.g., n-propyl and isopropyl), butyl (n-butyl, 2-butyl,isobutyl, or t-butyl), or pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R² is methyl. In certainembodiments, R² is C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, benzyl, phenoxy,benzoxy, or heterocyclyl. In certain embodiments, R² is —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein. In certain embodiments,R² is —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—OC(O)NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —^(1a)S(O)₂R^(1d), —S(O)₂R^(1a), or—S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b), R^(1c), and R^(1d) are eachas defined herein.

In certain embodiments, R¹ and R² are the same. In certain embodiments,R¹ and R² are fluoro. In certain embodiments, R¹ and R² are chloro. Incertain embodiments, R¹ and R² are methyl.

In certain embodiments, R¹ and R² are different. In certain embodiments,R¹ is fluoro, chloro, or methyl. In certain embodiments, R² is fluoro,chloro, or methyl.

In certain embodiments, R³ is hydrogen, halo, cyano, nitro, or hydroxyl.In certain embodiments, R³ is cyano or nitro. In certain embodiments, R³is C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl,alkoxy, and alkylthio are each independently and optionally substitutedwith one, two, or three halo. In certain embodiments, R³ is C₂₋₆alkenyl, C₂₋₆ alkynyl, or tetrazolyl. In certain embodiments, R³ is—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);wherein R^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein.In certain embodiments, R³ is —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), or —NR^(1a)C(O)OR^(1d); wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each as defined herein.

In certain embodiments, R⁴ is

wherein R⁵, Y, m, n, and p are each as defined herein; and R⁵ is notattached to Y. In certain embodiments, R⁴ is

wherein R^(1a), R^(1b), and R^(1c), are each as defined herein.

In certain embodiments, R⁵ is halo, cyano, nitro, hydroxyl, oxo, orguanidine. In certain embodiments, R⁵ is oxo. In certain embodiments, R⁵is C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl,alkoxy, and alkylthio are each independently and optionally substitutedwith one, two, or three halo. In certain embodiments, R⁵ is C₁₋₆ alkyl.In certain embodiments, R⁵ is methyl, ethyl, propyl (e.g., n-propyl andisopropyl), butyl (n-butyl, 2-butyl, isobutyl, or t-butyl), or pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl). Incertain embodiments, R⁵ is methyl. In certain embodiments, R⁵ is C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, benzyl, phenoxy, benzoxy, orheterocyclyl. In certain embodiments, R⁵ is —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1d)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or—S(O)₂NR^(1b)R^(1c); wherein R^(1a), R^(1b), R^(1c), and R^(1d) are eachas defined herein. In certain embodiments, R⁵ is C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —OC(O)NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), or NR^(1a)C(O)OR^(1d); wherein R^(1a), R^(1b),R^(c), and R^(1d) are each as defined herein. In certain embodiments, R⁵is C(O)OR^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R⁵ is —C(O)O—C₁₋₆ alkyl, optionally substituted with one ormore substituents. In certain embodiments, R⁵ is —C(O)O—C₁₋₆ alkyl. Incertain embodiments, R⁵ is methoxycarbonyl.

In certain embodiments, X is O. In certain embodiments. X is S.

In certain embodiments, Y is —O—. In certain embodiments, Y is —S—. Incertain embodiments, Y is —S(O)—. In certain embodiments, Y is —S(O)₂—.In certain embodiments. Y is —NR^(1a)—, wherein R^(1a) is as definedherein. In certain embodiments, Y is —C(R^(1a))(R^(1d))—, wherein R^(1a)and R^(1d) are each as defined herein. In certain embodiments, Y is—CR^(1a)NR^(1b)R^(1c)—, wherein R^(1a), R^(1b), and R^(1c) are each asdefined herein.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, m is 2. In certain embodiments, m is 3.

In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 3.

In certain embodiments, m is 1 and n is 1. In certain embodiments, m is1 and n is 2.

In certain embodiments, p is 0. In certain embodiments, p is 1. Incertain embodiments, p is 2. In certain embodiments, p is 3. In certainembodiments, p is 4.

In certain embodiments, r is 1. In certain embodiments, r is 2. Incertain embodiments, r is 3. In certain embodiments, r is 4. In certainembodiments, r is 5. In certain embodiments, r is 6.

In certain embodiments, R^(1a) is hydrogen. In certain embodiments,R^(1a) is phenyl or benzyl. In certain embodiments, R^(1a) is C₃₋₇cycloalkyl. In certain embodiments, R^(1a) is cyclopentyl or cyclohexyl.In certain embodiments, R^(1a) is heteroaryl or heterocyclyl, eachoptionally substituted. In certain embodiments, R^(1a) is3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl. In certain embodiments, R^(1a)is 5-butyl-7-chloro-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl. In certainembodiments, R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two,or three substituents, each independently selected from halo, hydroxyl,carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl. In certain embodiments, R^(1a) is alkyl. Incertain embodiments, R^(1a) is methyl, ethyl, propyl (e.g., n-propyl andisopropyl), butyl (n-butyl, 2-butyl, isobutyl, or t-butyl), or pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl). Incertain embodiments, R^(1a) is methyl, methyl, isopropyl, or 3-pentyl.

In certain embodiments, R^(1b) is hydrogen. In certain embodiments,R^(1b) is phenyl. In certain embodiments, R^(1b) is benzyl. In certainembodiments, R^(1b) is C₃₋₇ cycloalkyl. In certain embodiments, R^(1b)is cyclopentyl. In certain embodiments, R^(1b) is C₁₋₆ alkyl, optionallysubstituted with one, two, or three substituents, each independentlyselected from halo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl,C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl. C₃₋₇ cycloalkylcarbamoyl,and C₃₋₇ heterocyclylcarbamoyl. In certain embodiments, R^(1b) is C₁₋₆alkyl. In certain embodiments, R^(1b) is methyl, ethyl, propyl (e.g.,n-propyl and isopropyl), butyl (n-butyl, 2-butyl, isobutyl, or t-butyl),or pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1b) is methyl or ethyl.

In certain embodiments, R^(1c) is hydrogen. In certain embodiments,R^(1c) is phenyl. In certain embodiments, R^(1c) is benzyl. In certainembodiments, R^(1c) is C₃₋₇ cycloalkyl. In certain embodiments, R^(1c)is cyclopentyl. In certain embodiments, R^(1c) is C₁₋₆ alkyl, optionallysubstituted with one, two, or three substituents, each independentlyselected from halo, hydroxyl, carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl,C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl,and C₃₋₇ heterocyclylcarbamoyl. In certain embodiments, R^(1c) is C₁₋₆alkyl. In certain embodiments, R^(1c) is methyl, ethyl, propyl n-propyland isopropyl), butyl (n-butyl, 2-butyl, isobutyl, or t-butyl), orpentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1c) is methyl or ethyl.

In certain embodiments, R^(1b) and R^(1c) together with the N atom towhich they are attached form heteroaryl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl, optionally substituted with one or more substituentsQ as described herein. In certain embodiments, R^(1b) and R^(1c)together with the N atom to which they are attached form 5- to7-membered heteroaryl. In certain embodiments, R^(1b) and R^(1c)together with the N atom to which they are attached form 5- to7-membered heterocyclyl. In certain embodiments, R^(1b) and R^(1c)together with the N atom to which they are attached form 5-memberedheterocyclyl. In certain embodiments, R^(1b) and R^(1c) together withthe N atom to which they are attached form pyrrolidinyl. In certainembodiments, R^(1b) and R^(1c) together with the N atom to which theyare attached form 6-membered heterocyclyl. In certain embodiments,R^(1b) and R^(1c) together with the N atom to which they are attachedform piperidinyl.

In certain embodiments, R^(1d) is hydrogen. In certain embodiments,R^(1d) is phenyl or benzyl. In certain embodiments, R^(1d) is C₃₋₇cycloalkyl. In certain embodiments, R^(1d) is cyclopentyl. In certainembodiments, R^(1d) is C₁₋₆ alkyl, optionally substituted with one, two,or three substituents, each independently selected from halo, hydroxyl,carboxy, alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl. In certain embodiments, R^(1d) is C₁₋₆ alkyl. Incertain embodiments, R^(1d) is methyl, ethyl, propyl (e.g., n-propyl andisopropyl), butyl (n-butyl, 2-butyl, isobutyl, or t-butyl), or pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl). Incertain embodiments, R^(1d) is methyl, isopropyl, or 3-pentyl. Incertain embodiments, R^(1d) is 1-hydroxyl-isopropyl.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

and enantiomers, mixtures of enantiomers, mixtures of two or morediastereomers, tautomers, and mixtures of two or more tautomers thereof;and pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

In one embodiment, the compound provided here is a hydrochloride salt.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Methods of Synthesis

The compound provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art. For an example, a compoundof Formula I can be prepared as shown in Scheme 1. Nitrobenzene 1 reactswith compound 2 via aromatic substitution reaction in the presence of abase, such as potassium carbonate, to form nitrobiaryl 3. Subsequently,the nitrobiaryl 3 is reduced with a reducing agent, such as TiCl₂ orsodium hydrosulfite, to aminobiaryl 4, which is then converted tosulfonyl chloride 5 via the Sandmeyer reaction. A compound of Formula Iis formed by reacting sulfonyl chloride 5 with R⁴H in the presence of abase, such as triethylamine.

A compound of Formula I can also be prepared as shown in Scheme 2.Aniline 6 is first converted into sulfonyl chloride 7 via the Sandmeyerreaction. Subsequently, sulfonyl chloride 7 reacts with R⁴H in thepresence of a base, such as triethylamine, to form chlorobenzene 8,which then reacts with compound 2 via aromatic substitution reaction inthe presence of a base, such as potassium carbonate, to form a compoundof Formula I.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compoundprovided herein, e.g., a compound of Formula I, as an active ingredient,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; in combination with a pharmaceutically acceptablevehicle, carrier, diluent, or excipient, or a mixture thereof.

The compound provided herein may be administered alone, or incombination with one or more other compounds provided herein. Thepharmaceutical compositions that comprise a compound provided herein,e.g., a compound of Formula I, can be formulated in various dosage formsfor oral, parenteral, and topical administration. The pharmaceuticalcompositions can also be formulated as modified release dosage forms,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated-, fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art (see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al.,Eds., Marcel Dekker, Inc.: New York, N.Y., 2008).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, e.g., a compound of Formula I, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and one or more pharmaceutically acceptable excipients or carriers.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, including an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and one or more pharmaceutically acceptable excipients or carriers.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, including an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and one or more pharmaceutically acceptable excipients or carriers.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate. CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS. HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709.874.

Methods of Use

In one embodiment, provided is a method of treating, preventing, orameliorating one or more symptoms of a disorder, disease, or conditionassociated with CCR3 in a subject, which comprises administering to thesubject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

In another embodiments, provided is a method of treating, preventing, orameliorating one or more symptoms of a disorder, disease, or conditionresponsive to the modulation of CCR3 activity in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the subject is a mammal. In anotherembodiment, the subject is a human.

In yet another embodiment, provided is a method of treating, preventing,or ameliorating one or more symptoms of a disorder, disease, orcondition mediated by a CCR3 receptor in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the subject is a mammal. In anotherembodiment, the subject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of aneosinophil-related disorder, disease, or condition in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof. In one embodiment, the subject is a mammal. In anotherembodiment, the subject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of a basophil-relateddisorder, disease, or condition in a subject, comprising administeringto a subject, a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of a mast cell-relateddisorder, disease, or condition in a subject, comprising administeringto a subject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

In yet another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of an inflammatorydisease in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula I, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In oneembodiment, the subject is a mammal. In another embodiment, the subjectis a human.

The disorders, diseases, or conditions treatable with a compoundprovided herein, e.g., a compound of Formula I, including an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,include, but are not limited to, (1) inflammatory or allergic diseases,including systemic anaphylaxis and hypersensitivity disorders, atopicdermatitis, urticaria, drug allergies, insect sting allergies, foodallergies (including celiac disease and the like), and mastocytosis; (2)inflammatory bowel diseases, including Crohn's disease, ulcerativecolitis, ileitis, and enteritis; (3) vasculitis, and Behcet's syndrome;(4) psoriasis and inflammatory dermatoses, including dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria, viralcutaneous pathologies including those derived from human papillomavirus,HIV or RLV infection, bacterial, flugal, and other parasital cutaneouspathologies, and cutaneous lupus erythematosus; (5) asthma andrespiratory allergic diseases, including allergic asthma, exerciseinduced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the disorder, disease, or condition is selectedfrom the group consisting of asthma, allergic asthma, exercise inducedasthma, allergic rhinitis, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, contact hypersensitivity, contactdermatitis, conjunctivitis, allergic conjunctivitis, eosinophilicbronchitis, food allergies, eosinophilic gastroenteritis, inflammatorybowel disease, ulcerative colitis. Crohn's disease, mastocytosis, hyperIgE syndrome, systemic lupus erythematous, psoriasis, acne, multiplesclerosis, allograft rejection, reperfusion injury, chronic obstructivepulmonary disease, Churg-Strauss syndrome, sinusitis, basophilicleukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema,COPD (chronic obstructive pulmonary disorder), arthritis, rheumatoidarthritis, psoriatic arthritis, and osteoarthritis.

In certain embodiments, the disorder, disease, or condition is asthma,exercise induced asthma, allergic rhinitis, atopic dermatitis, chronicobstructive pulmonary disease, or allergic conjunctivitis.

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided is administration of the compounds orpharmaceutical compositions provided herein in a depot formulation, inwhich the active ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofasthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever,sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis,multiple sclerosis, atherosclerosis, transplant rejection, inflammatorybowel disease, cancer, or other conditions, disorders or diseasesassociated with a CCR3 receptor, an appropriate dosage level generallyis ranging from about 0.001 to 100 mg per kg subject body weight per day(mg/kg per day), from about 0.01 to about 75 mg/kg per day, from about0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day,or from about 1 to about 20 mg/kg per day, which can be administered insingle or multiple doses. Within this range, the dosage can be rangingfrom about 0.005 to about 0.05, from about 0.05 to about 0.5, from about0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, orfrom about 1 to about 50 mg/kg per day. In certain embodiments, thedosage level is ranging from about 0.001 to about 100 mg/kg per day. Incertain embodiments, the dosage level is ranging from about 0.01 toabout 75 mg/kg per day. In certain embodiments, the dosage level isranging from about 0.1 to about 50 mg/kg per day. In certainembodiments, the dosage level is ranging from about 0.5 to about 25mg/kg per day. In certain embodiments, the dosage level is ranging fromabout 1 to about 20 mg/kg per day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Also provided herein are methods of modulating CCR3 activity, comprisingcontacting a CCR3 receptor with a compound provided herein, e.g., acompound of Formula I, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In oneembodiment, the CCR3 receptor is expressed by a cell.

The compounds provided herein, e.g., a compound of Formula I, includingan enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof, can also be combined or used in combination with otheragents useful in the treatment, prevention, or amelioration of one ormore symptoms of the disorders, diseases, or conditions for which thecompounds provided herein are useful, including asthma, allergicrhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemiclupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis,atherosclerosis, transplant rejection, inflammatory bowel disease,cancer, infectious diseases, and those pathologies noted above.

In certain embodiments, the compounds provided herein can be combinedwith one or more steroidal drugs known in the art, including, but notlimited to the group including, aldosterone, beclometasone,betamethasone, deoxycorticosterone acetate, fludrocortisone,hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone,dexamethasone, and triamcinolone.

In certain embodiments, the compounds provided herein can be combinedwith one or more antibacterial agents known in the art, including, butnot limited to the group including amikacin, amoxicillin, ampicillin,arsphenamine, azithromycin, aztreonam, azlocillin, bacitracin,carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin,cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime,cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin,clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin,demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin,enrofloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin,furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimycin,imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin,loracarbef, mafenide, moxifloxacin, meropenem, metronidazole,mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin,nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin,piperacillin, platensimycin, polymyxin B, prontocil, pyrazinamide,quinupristine, rifampin, roxithromycin, spectinomycin, streptomycin,sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin,telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim,troleandomycin, trovafloxacin, and vancomycin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antifungal agents known in the art, including, but notlimited to the group including amorolfine, amphotericin B,anidulafungin, bifonazole, butenafine, butoconazole, caspofungin,ciclopirox, clotrimazole, econazole, fenticonazole, filipin,fluconazole, isoconazole, itraconazole, ketoconazole, micafungin,miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole,posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine,terconazole, tioconazole, and voriconazole.

In certain embodiments, the compounds provided herein can be combinedwith one or more anticoagulants known in the art, including, but notlimited to the group including acenocoumarol, argatroban, bivalirudin,lepirudin, fondaparinux, heparin, phenindione, warfarin, andximelagatran.

In certain embodiments, the compounds provided herein can be combinedwith one or more thrombolytics known in the art, including, but notlimited to the group including anistreplase, reteplase, t-PA (alteplaseactivase), streptokinase, tenecteplase, and urokinase.

In certain embodiments, the compounds provided herein can be combinedwith one or more non-steroidal anti-inflammatory agents known in theart, including, but not limited to, aceclofenac, acemetacin, amoxiprin,aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,choline magnesium salicylate, diclofenac, diflunisal, etodolac,etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib,meclofenamic acid, mefenamic acid, meloxicam, metamizole, methylsalicylate, magnesium salicylate, nabumetone, naproxen, nimesulide,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenicacid, and tolmetin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antiplatelet agents known in the art, including, butnot limited to, abciximab, cilostazol, clopidogrel, dipyridamole,ticlopidine, and tirofibin.

The compounds provided herein can also be administered in combinationwith other classes of compounds, including, but not limited to,endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon;thromboxane receptor antagonists, such as ifetroban; potassium channelopeners; thrombin inhibitors, such as hirudin; growth factor inhibitors,such as modulators of PDGF activity; platelet activating factor (PAF)antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g.,clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, suchas warfarin; low molecular weight heparins, such as enoxaparin; FactorVIIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutralendopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACEinhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductaseinhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522(also known as rosuvastatin, atavastatin, or visastatin); squalenesynthetase inhibitors; fibrates; bile acid sequestrants, such asquestran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors;MTP Inhibitors; calcium channel blockers, such as amlodipine besylate;potassium channel activators; alpha-adrenergic agents; beta-adrenergicagents, such as carvedilol and metoprolol; antiarrhythmic agents;diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid,ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide,triamterene, amiloride, and spironolactone; thrombolytic agents, such astissue plasminogen activator (tPA), recombinant tPA, streptokinase,urokinase, prourokinase, and anisoylated plasminogen streptokinaseactivator complex (APSAC); anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrimidine analogues; antibiotics, such asanthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin;enzymes, such as L-asparaginase; farnesyl-protein transferaseinhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone antagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathioprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxiband rofecoxib; and miscellaneous agents such as, hydroxyurea,procarbazine, mitotane, hexamethylmelamine, gold compounds, platinumcoordination complexes, such as cisplatin, satraplatin and carboplatin.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with thecompounds provided herein, e.g., a compound of Formula I, including asingle enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof. When a compound provided herein is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compoundprovided herein can be utilized, but is not required. Accordingly, thepharmaceutical compositions provided herein include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a compound provided herein.

The weight ratio of a compound provided herein to the second activeingredient can be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound to the NSAID can range fromabout 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.Combinations of a compound provided herein and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, including a single enantiomer or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar);eq. (equivalent); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr orhrs (hours); min (minutes); MS (mass spectrometry); ESI (electrosprayionization); TLC (thin layer chromatography); R_(t) (retention time);SiO₂ (silica); THF (tetrahydrofuran); DCM (dichloromethane); DMSO(dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); EtOAc(ethyl acetate); EtOH (ethanol); Et₂O, (diethylether); HCl (hydrochloricacid); K₂CO₃ (potassium carbonate); NaOH, (sodium hydroxide); Na₂SO₄(sodium sulfate); NaCl, (sodium chloride); MgSO₄ (magnesium sulfate);NaH (sodium hydride); NaHCO₃ (sodium bicarbonate); TEA (triethylamine);NaNO₂, (sodium nitrite); CuCl₂, (copper(II) chloride); SO₂, (sulfurdioxide); Me (methyl); Et (ethyl); tBu (tert-butyl); and Boc(tert-butoxylcarbony).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1 Preparation of4-(2,5-difluorophenoxy)-3-(4-(dimethylamino)piperidin-1-ylsulfonyl)benzonitrile

Compound 59 was synthesized as shown in Scheme 3.

4-(2,5-Difluorophenoxy)-3-nitrobenzonitrile 21. A solution of4-chloro-3-nitrobenzonitrile (5 g) in THF (200 mL) at room temperaturewas treated with K₂CO₃ (19 g), followed by 2,5-difluorophenol (3.7 g).After stirring at room temperature for 18 hrs, the solid was filteredoff and rinsed with copious amounts of EtOAc. The filtrate was washedsequentially with saturated aqueous NaHCO₃ solution, water, andsaturated aqueous NaCl solution, dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residual was triturated with hexanes andcollected by suction to furnish the desired product 21, which was useddirectly in the next step without further purification.

3-Amino-4-(2,5-difluorophenoxy)benzonitrile 22. A mixture of Tin (II)chloride dihydrate (18.238 g, 81.00 mmol) in EtOH (65.00 mL) and HCl (12M, 10.00 mL) was stirred at 70° C. until the solution became clear.Compound 21 (5.60 g, 20.28 mmol) was then added over 10 min. Thesolution was kept slightly refluxing during addition. The reaction wasmonitored with TCL (25% EtOAc in hexanes, R_(f)=0.65). The reaction wascomplete after refluxing for 1.5 hrs, as indicated by the absence of thestarting material (TLC). Water (80 mL) was added and the resultingsolution was allowed to cool to room temperature. The desired productwas precipitated out as a white solid during cooling. The mixture wasfurther cooled and stirred for 30 min at 15° C. The resultingprecipitation was collected via filtration under vacuum, washed withwater, and dried under vacuum to yield compound 22 as a white solid(3.60 g, 99.0% HPLC purity, 63% yield). ¹H NMR (500 MHz, DMSO-d₆): δ7.44 (m, 1H), 7.09 (m, 2H), 7.04 (m, 1H), 6.92 (dd, J₁=2 Hz, J₂=8 Hz,1H), 6.78 (d, J=8 Hz, 1H), 5.65 (s, 2H).

5-Cyano-2-(2,5-difluorophenoxy)benzene-1-sulfonyl chloride 23. To asolution of compound 22 (4.20 g, 14.86 mmol) in acetic acid (50.00 mL)was added HCl (12 M, 40.00 mL). The solution was stirred in an ice bath.A solution of NaNO₂ (1.230 g, 17.83 mmol) in water (5 mL) was addeddropwise to the compound 22 containing solution with stirring. Thereaction mixture was stirred in an ice bath for additional 2 hrs. In aseparate flask, SO₂ was bubbled through acetic acid (100 mL) for 45 minto form a SO₂ saturated solution. CuCl₂ (1.267 g, 7.43 mmol) was thenadded to the SO₂ saturated solution and stirred for an additional 15min. The CuCl₂ solution was then cooled with an ice bath and stirred for10 min. The solution containing compound 22 was then added dropwise intothe CuCl₂ solution. After the addition, the solution was stirred foradditional 45 min, and then poured onto ice water and stirred for 1 hr.The resulting orange precipitate was collected through filtration. Thesolid (3.5 g) was dissolved in minimal amount of DCM and purified withchromatography eluted with DCM. Pure fractions were combined andevaporated in vacuo. The resulting solid was triturated with DCM andhexanes, and filtered to obtain compound 23 as a yellow/white solid(0.600 g, 95% HPLC purity, 12.2% yield). A second trituration of thefiltrate yielded 150 mg of impure product.

4-(2,5-Difluorophenoxy)-3-(4-(dimethylamino)piperidin-1-ylsulfonyl)benzonitrile59. To a solution of compound 23 (0.080 g, 0.24 mmol) in DCM (10.00 mL)was added 4-dimethylaminopiperidine (0.040 g, 0.31 mmol) and TEA (0.043g, 0.31 mmol). The reaction was monitored with TLC (25% EtOAc inhexanes, Rf=0.0). The reaction was complete after stirring at roomtemperature for 30 min, as indicated by the absence of the startingmaterial (TLC). Water was then added and extracted twice with DCM.Combined organic extracts were washed sequentially with water and brine,dried over MgSO₄, filtered, and evaporated in vacuo to form a yellowoil. The oil was triturated with DCM and hexanes, and filtered to yieldcompound 59 as a white powder (0.85 g, 97.4% HPLC purity, 84% yield). ¹HNMR (500 MHz, DMSO-d₆): δ 8.27 (d, J=2 Hz, 1H), 8.08 (dd, J₁=2 Hz, J₂=8Hz, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.26 (m, 1H), 7.19 (d, J=9 Hz, 1H),3.71 (d, J=13 Hz, 2H), 2.77 (t, J=13 Hz, 2H), 2.18 (m, 1H), 2.12 (s,3H), 1.76 (d, J=11 Hz, 2H), 1.35 (m, 2H); MS (ESI, EI⁺): m/z=422 (MH⁺);melting point: 154-157° C.

4-(2,5-Difluorophenoxy)-3-(4-(dimethylamino)piperidin-1-ylsulfonyl)benzonitrile,hydrochloride 59. To a solution of neutral compound 59 (25.0 mg, 0.06mmol) in 1,4-dioxane (2.0 mL) was added 4 N HCl in 1,4-dioxane (60.0 μL,0.24 mmol). The reaction mixture was stirred for 10 min at roomtemperature before adding 2 mL of diethyl ether. A white precipitateformed and collected via filtration to obtain compound 59 hydrochlorideas a white solid (25.0 mg, 100% HPLC purity, 91% yield). ¹H NMR (500MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.30 (d, J=2 Hz, 1H), 8.10 (dd, J₁=2 Hz,J₂=8 Hz, 1H), 7.55 (m, 1H), 7.47 (m, 1H), 7.28 (m, 1H), 7.20 (d, J=8 Hz,1H), 3.89 (m, 2H), 3.25 (m, 1H), 2.78 (t, J₁=J₂=12 Hz, 2H), 2.68 (s,6H), 2.11 (m, 2H), 1.64 (m, 2H); MS (ESI, EI⁺): m/z=422 (MH⁺); meltingpoint: 250-252° C.

The following compounds were made according to the procedures asdescribed in this example.

4-(2,5-Difluorophenoxy)-3-(piperazin-1-ylsulfonyl)benzonitrile,dihydrochloride 52. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.41(s, 2H), 8.31 (d, J=2 Hz, 1H), 8.13 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.55 (m,2H), 7.29 (m, 1H), 7.21 (d, J=8 Hz, 1H), 3.50 (m, 4H), 3.16 (m, 4H); MS(ESI, EI⁺): m/z=380 (MH⁺); melting point: 125-143° C.

4-(2,5-Difluorophenoxy)-3-(3,5-dimethylpiperazin-1-ylsulfonyl)benzonitrile53. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.27 (d, J=2 Hz,1H), 8.09 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.56 (m, 1H), 7.35 (m, 1H), 7.24(m, 2H), 3.55 (m, 2H), 2.69 (m, 2H), 2.17 (t, J₁=J₂=11 Hz, 3H), 0.91 (d,J=8 Hz, 6H); MS (ESI, EI⁺): m/z=408 (MH⁺); melting point: 157-159° C.

4-(2,5-Difluorophenoxy)-3-(3,5-dimethylpiperazin-1-ylsulfonyl)benzonitrile,dihydrochloride 53. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.50(m, 1H), 9.26 (m, 1H), 8.31 (d, J=2 Hz, 1H), 8.13 (dd, J₁=2 Hz, J₂=8 Hz,1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.28 (m, 1H), 7.23 (d, J=8 Hz, 1H),3.87 (m, 2H), 2.89 (t. J₁=J₂=12 Hz, 2H), 1.23 (d, J=6 Hz, 6H); MS (ESI,EI⁺): m/z=408 (MH⁺).

4-(2,5-Difluorophenoxy)-3-(4-isopropylpiperazin-1-ylsulfonyl)benzonitrile54. HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz, 1H),8.09 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.56 (m, 1H), 7.42 (m, 1H), 7.25 (m,1H), 7.21 (d, J=8 Hz, 1H), 3.18 (m, 4H), 2.65 (m, 1H), 2.46 (m, 4H),0.92 (d, J=7 Hz, 6H); melting point: 179-182° C.

4-(2,5-Difluorophenoxy)-3-(4-isopropylpiperazin-1-ylsulfonyl)benzonitrile,hydrochloride 54. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 11.00(s, 1H), 8.33 (d, J=2 Hz, 1H), 8.12 (dd. J₁=2 Hz, J₂=8 Hz, 1H), 7.64 (m,1H), 7.57 (m, 1H), 7.30 (m, 1H), 7.20 (d, J=8 Hz, 1H), 3.88 (m, 2H),3.48 (m, 3H), 3.40 (m, 2H), 3.08 (m, 2H), 1.26 (d, J=7 Hz, 6H); MS (ESI,EI⁺): m/z=422 (MH⁺).

4-(2,5-Difluorophenoxy)-3-(4-(pentan-3-yl)piperazin-1-ylsulfonyl)benzonitrile55. HPLC purity: 97%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz, 1H),8.09 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.56 (m, 1H), 7.39 (m, 1H), 7.26 (m,1H), 7.21 (d, J=8 Hz, 1H), 3.16 (m, 4H), 2.50 (m, 4H), 2.13 (m, 1H),1.37 (m, 2H), 1.22 (m, 2H), 0.81 (t, J₁=J₂=7 Hz, 6H); melting point:107-109° C.

4-(2,5-Difluorophenoxy)-3-(4-(pentan-3-yl)piperazin-1-ylsulfonyl)benzonitrile,hydrochloride 55. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.72(s, 1H), 8.32 (d, J=2 Hz, 1H), 8.13 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.67 (m,1H), 7.57 (m, 1H), 7.30 (m, 1H), 7.21 (d, J=8 Hz, 1H), 3.84 (m, 2H),3.49 (m, 4H), 3.06-3.17 (m, 3H), 1.83 (m, 2H), 1.61 (m, 2H), 0.94 (t,J₁=J2=7 Hz, 6H); MS (ESI, EI⁺): m/z=450 (MH⁺); melting point: 206-209°C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-difluorophenoxy)benzonitrile56. HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz, 1H),8.09 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.56 (m, 1H), 7.43 (m, 1H), 7.26 (m,1H), 7.20 (d, J=8 Hz, 1H), 3.19 (m, 4H), 2.46 (m, 5H), 1.72 (m, 2H),1.56 (m, 2H), 1.47 (m, 2H), 1.26 (m, 2H); MS (ESI, EI⁺): m/z=448 (MH⁺);melting point: 158-160° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-difluorophenoxy)benzonitrile,hydrochloride 56. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 11.06(s, 1H), 8.32 (d, J=2 Hz, 1H), 8.13 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.60 (m,2H), 7.30 (m, 1H), 7.21 (d, J=8 Hz, 1H), 3.87 (m, 2H), 3.52 (m, 3H),3.32 (m, 2H), 3.10 (m, 2H), 1.97 (m, 2H), 1.72 (m, 4H), 1.53 (m, 2H); MS(ESI, EI⁺): m/z=448 (MH⁺).

4-(2,5-Difluorophenoxy)-3-(4-methyl-1,4-diazepan-1-ylsulfonyl)benzonitrile,hydrochloride 57. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.68(s, 1H), 8.30 (d, J=2 Hz, 1H), 8.09 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.58 (m,1H), 7.52 (m, 1H), 7.30 (m, 1H), 7.18 (d, J=8 Hz. I H), 3.88 (, 1H),3.49-3.59 (m, 4H), 3.36 (m, 1H), 3.26 (m, 1H), 3.18 (m, 1H), 2.79 (s,3H), 2.15 (m, 2H); MS (ESI, EI⁺): m/z=408 (MH⁺); melting point: 238-242°C.

4-(2,5-Difluorophenoxy)-3-(morpholinosulfonyl)benzonitrile 58. HPLCpurity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz, 1H), 8.10(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.57 (m, 1H), 7.47 (m, 1H), 7.27 (m, 1H),7.20 (d, J=8 Hz, 1H), 3.62 (m, 4H), 3.20 (m, 4H); melting point:165-168° C.

4-(2,5-Difluorophenoxy)-3-(4-(pyrrolidin-1-ylpiperidin-1-ylsulfonyl)benzonitrile60. HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.27 (d, J=2 Hz, 1H),8.08 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.55 (m, 1H), 7.38 (m, 1H), 7.25 (m,1H), 7.20 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 3.60 (m, 2H), 2.87 (m, 2H), 2.44(m, 4H), 2.10 (s, 1H), 1.85 (m, 2H), 1.64 (m, 4H), 1.40 (m, 2H); MS(ESI, EI⁺): m/z=448 (MH⁺); melting point: 189-192° C.

4-(2,5-Difluorophenoxy)-3-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)benzonitrile,hydrochloride 60. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.92(m, 1H), 8.30 (d, J=2 Hz, 1H), 8.09 (dd, J₁=2 Hz, J₂=8 Hz, 1H),7.49-7.58 (m, 2H), 7.29 (m, 1H), 7.20 (d, J=8 Hz, 1H), 3.86 (m, 2H),3.44 (m, 2H), 3.20 (m, 1H), 3.00 (m, 2H), 2.78 (t, J₁=J₂=12 Hz, 2H),2.12 (m, 2H), 1.92 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H); MS (ESI, EI⁺):m/z=448 (MH⁺); melting point: 260-263° C.

5-Cyano-N-(2-(diethylamino)ethyl)-2-(2,5-difluorophenoxy)benzenesulfonamide,hydrochloride 62. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.47(s, 1H), 8.39 (t, J₁=J₂=6 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 8.08 (dd, J₁=2Hz, J₂=8 Hz, 1H), 7.55 (m, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.12 (d, J=8Hz, 1H), 3.30 (m, 2H), 3.14 (m, 6H), 1.20 (t, J₁=J₂=7 Hz, 6H); MS (ESI,EI⁺): m/z=410 (MH⁺); melting point: 180-182° C.

5-Cyano-2-(2,5-difluorophenoxy)-N-(2-(pyrrolidin-1-yl)ethyl)benzenesulfonamide63. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz,1H), 8.02 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.56 (m, 1H), 7.36 (m, 1H), 7.27(m, 1H), 7.07 (d, J=8 Hz, 1H), 3.06 (t, J₁=J₂=7 Hz, 2H), 2.42 (t,J₁=J₂=7 Hz, 2H), 2.29 (s, 4H), 1.56 (s, 4H); MS (ESI, EI⁺): m/z=408(MH⁺); melting point: 122-125° C.

5-Cyano-2-(2,5-difluorophenoxy)-N-(2-(pyrrolidin-1-yl)ethyl)benzenesulfonamide,hydrochloride 63. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.46(s, 1H), 8.38 (m, 1H), 8.27 (d, J=2 Hz, 1H), 8.08 (dd, J₁=2 Hz, J₂=8 Hz,1H), 7.55 (m, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.12 (d, J=7 Hz, 1H),3.55 (m, 2H), 3.26 (m, 4H), 3.00 (m, 2H), 1.98 (m, 2H), 1.86 (m, 2H); MS(ESI, EI⁺): m/z=408 (MH⁺); melting point: 229-232° C.

5-Cyano-2-(2,5-difluorophenoxy)-N-(2-(piperidin-1-yl)ethyl)benzenesulfonamide64. HPLC purity: 99.5%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.25 (d, J=2 Hz,1H), 8.03 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.8-7.9 (stretched peak, 1H), 7.56(m, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 7.10 (dd, J₁=2 Hz, J₂=8 Hz, 1H),3.03 (t, J₁=J₂=7 Hz, 2H), 2.29 (t, J₁=J₂=7 Hz, 2H), 2.21 (s, 4H),1.24-1.38 (m, 6H); MS (ESI, EI⁺): m/z=422 (MH⁺); melting point: 70-80°C.

5-Cyano-2-(2,5-difluorophenoxy)-N-(2-(piperidin-1-yl)ethyl)benzenesulfonamide,hydrochloride 64. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.10(s, 1H), 8.38 (t. J₁=J₂=6 Hz, 1H), 8.26 (d, J=2 Hz, 1H), 8.08 (dd, J₁=2Hz, J₂=8 Hz, 1H), 7.55 (m, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.12 (d, J=7Hz, 1H), 3.42 (m, 2H), 3.32 (m, 2H), 3.14 (m, 2H), 2.89 (m, 2H),1.66-1.78 (m, 5H), 1.36 (m, 1H); MS (ESI, EI⁺): m/z=422 (MH⁺); meltingpoint: 210-213° C.

Example 2 Preparation of3-(4-(dimethylamino)piperidin-1-ylsulfonyl)-4-(2,5-dimethylphenylthio)benzonitrile

Compound 72 was synthesized as shown in Scheme 4.

4-(2,5-Dimethylphenylthio)-3-nitrobenzonitrile 24. To a solution of4-chloro-3-nitrobenzonitrile (5.4 g, 29.67 mmol) in THF (100 mL) wasadded 2,5-dimethylthiophenol (4.921 g, 35.60 mmol) and K₂CO₃ (20.45 g,148.0 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes).After refluxing for 16 hrs, the reaction was complete. The solid wasfiltered and washed with copious amounts of EtOAc. The filtrate waswashed sequentially with saturated NaHCO₃, water, saturated NaClsolution, dried over MgSO₄, filtered, and evaporated in vacuo. Theresulting solid was then sonicated in hexanes and filtered to yieldcompound 24 as a yellow/white solid (8.00 g, 97.8% HPLC purity, 95%yield). ¹H NMR (500 MHz, DMSO-d₆): δ8.77 (d, J=2 Hz, 1H), 7.94 (dd, J₁=2Hz, J₂=8 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=8 Hz, 1H), 7.36 (d, J=8 Hz,1H), 6.76 (d, J=8 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H).

3-Amino-4-(2,5-dimethylphenylthio)benzonitrile 25. A mixture of Tin (II)chloride dihydrate (25.218 g, 112.0 mmol) in EtOH (85.0 mL) and conc.HCl (12 M, 15.0 mL) was stirred at 70° C. until a clear solution wasformed. Compound 24 (8.0 g, 28.14 mmol) was then added over 10 min. Thesolution was kept slightly refluxing during addition. The reaction wasmonitored with TLC (25% EtOAc in hexanes, R_(f)=0.65). The reaction wascomplete after refluxing for 1.5 hrs as indicated by the absence of thestarting material (TLC). Water (35 mL) was added and the resultingsolution was allowed to cool to room temperature. Precipitation occurredduring cooling. The mixture was further cooled and stirred for 30 min at15° C. The precipitate was filtered, washed with water, and dried undervacuum to yield compound 25 as a white solid (5.30 g, 95% HPLC purity,65% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 7.20 (d, J=8 Hz, 1H), 7.07 (d,J=2 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 6.90 (dd, J₁=2Hz, J₂=8 Hz, 1H), 6.85 (s, 1H), 5.72 (s, 2H), 2.26 (s, 3H), 2.18 (s,3H).

5-Cyano-2-(2,5-dimethylphenylthio)benzene-1-sulfonyl chloride 26. To asolution of compound 25 (5.00 g, 17.19 mmol) in acetic acid (80 mL) wasadded hydrochloric acid ((12 M, 50.0 mL). The mixture was stirred in anice bath. A solution of NaNO₂ (2.97 g, 43.00 mmol) in water (7 mL) wasadded dropwise to the compound 25-containing solution stirred in an icebath. After addition, the resulting solution was stirred in an ice bathfor 1 hr. In a separate flask, SO₂ was bubbled through acetic acid (40mL) for 45 min at room temperature to form a saturated SO₂ solution.Copper II chloride dihydrate (1.47 g, 8.60 mmol) was then added to theSO₂ saturated solution and stirred for an additional 15 min. Thesaturated SO₂ solution was then cooled with an ice bath and stirred for10 min. The compound 25-containing solution was then added dropwise intothe SO₂ saturated solution. After the addition, the solution was stirredfor additional 45 min. The reaction mixture was then poured onto icewater and stirred for 1 hr. The resulting precipitate was filtered toyield compound 26 as an orange solid (2.00 g, 65% HPLC purity, 35%yield).

3-(4-(Dimethylamino)piperidin-1-ylsulfonyl)-4-(2,5-dimethylphenylthio)-benzonitrile72. To a solution of compound 26 (0.200 g, 0.59 mmol) in DCM was addedTEA (0.090 g, 0.89 mmol) and 4-dimethylaminopiperidine (0.114 g, 0.89mmol). The reaction was monitored by HPLC. The reaction was completeafter stirring at room temperature for 16 hrs. DCM was removed in vacuo,and the resulting solid was dissolved in a minimal amount of DCM andpurified with chromatography with a gradient of 10 to 30% MeOH in DCM.Pure fractions were combined and evaporated in vacuo to yield an oil,which was triturated with DCM and hexanes, and then filtered to yieldcompound 72 as a peach solid (0.124 g, 49% yield). HPLC purity: 96.5%;¹H NMR (500 MHz, DMSO-d₆): δ 8.22 (d, J=2 Hz, 1H), 7.84 (dd, J₁=2 Hz,J₂=8 Hz, 1H), 7.41 (d, J=6 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J=8 Hz, 1H),6.70 (d, J=8 Hz, 1H), 3.8 (d, J=13 Hz, 2H), 2.84 (t, J=12 Hz, 2H), 2.31(s, 3H), 2.26 (m, 1H), 2.25 (s, 3H), 2.15 (s, 6H), 1.79 (d, J=12 Hz,2H), 1.43 (m, 2H); MS (ESI, EI⁺): m/z=430 (MH⁺); melting point: 136-139°C.

3-(4-(Dimethylamino)piperidin-1-ylsulfonyl)-4-(2,5-dimethylphenylthio)-benzonitrile,hydrochloride 72. To a solution of neutral compound 72 (30.0 mg, 0.07mmol) in 1,4-dioxane (2.0 mL) and added 4 N HCl in 1,4-dioxane (60.0 μL,0.24 mmol). The reaction mixture was stirred for 10 min at roomtemperature before adding 2 mL of diethyl ether. A white precipitate wasformed and collected via filtration to obtain compound 72 hydrochlorideas a white solid (32.0 mg, 97.6% HPLC purity, 100% yield). ¹H NMR (500MHz, DMSO-d₆): δ 10.62 (m, 1H), 8.24 (d, J=2 Hz, 1H), 7.86 (dd, J₁=2 Hz,J₂=8 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H),6.71 (d, J=8 Hz, 1H), 3.96 (m, 2H), 3.31 (m, 1H), 2.84 (m, 2H), 2.70 (d,J=5 Hz, 2.32 (s, 3H), 2.23 (s, 3H), 2.13 (m, 2H), 1.68 (m, 2H); MS (ESI,EI⁺): m/z=430 (MH⁺); melting point: 242-244° C.

The following compounds were made according to the procedures asdescribed in this example.

4-(2,5-Dimethylphenylthio)-3-(piperazin-1-ylsulfonyl)benzonitrile 65.HPLC purity: 98.7%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.19 (s, 1H), 7.85 (dd,J₁=2 Hz, J₂=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J₇=8Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.15 (m, 4H), 2.75 (m, 4H), 2.32 (s, 3H),2.23 (s, 3H); MS (ESI, EI⁺): m/z=388 (MH⁺); melting point: 192-195° C.

Tert-butyl-4-(5-cyano-2-(2,5-dimethylphenylthio)phenylsulfonyl)piperazine-1-carboxylate.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.20 (d, J=2 Hz, 1H),7.85 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J=8 Hz, 1H),7.33 (d, J=8 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.42 (m, 4H), 3.26 (m, 4H),2.31 (s, 3H), 2.22 (s, 3H), 1.38 (s, 9H); MS (ESI, EI⁺): m/z=430 (MH⁺).

4-(2,5-Dimethylphenylthio)-3-(3,5-dimethylpiperazin-1-ylsulfonyl)-benzonitrile66. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.20 (s, 1H), 7.84(d, J=8 Hz, 1H), 7.40 (d, J=9 Hz, 2H), 7.34 (d, J=8 Hz, 1H), 6.69 (d,J=8 Hz, 1H), 3.66 (d, J=12 Hz, 2H), 2.73 (m, 2H), 2.32 (s, 3H), 2.21 (s,3H), 2.19 (s, 1H), 2.17 (s, 2H), 0.95 (d, J=6 Hz, 6H); MS (ESI, EI⁺):m/z=416 (MH⁺); melting point: 161-164° C.

4-(2,5-Dimethylphenylthio)-3-(4-isopropylpiperazin-1-ylsulfonyl)benzonitrile67. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.20 (d, J=2 Hz,1H), 7.85 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.40 (m, 2H), 7.33 (m, 1H), 6.70(d, J=8 Hz, 1H), 3.24 (s, 4H), 2.68 (m, 1H), 2.31 (s, 3H), 2.23 (s, 3H),0.94 (d, J=7 Hz, 6H); MS (ESI, EI⁺): m/z=430 (MH⁺); melting point:148-151° C.

4-(2,5-Dimethylphenylthio)-3-(4-isopropylpiperazin-1-ylsulfonyl)benzonitrile,hydrochloride 67. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.92(s, 1H), 8.28 (d, J=2 Hz, 1H), 7.90 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.47 (s,1H), 7.41 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 6.74 (d, J=8 Hz, 1H),3.99 (m, 2H), 3.50 (m, 2H), 3.38 (m, 2H), 3.11 (m, 2H), 2.32 (s, 3H),2.25 (s, 3H), 1.27 (d, J=7 Hz, 6H); MS (ESI, EI⁺): m/z=430 (MH⁺).

4-(2,5-Dimethylphenylthio)-3-(4-(pentan-3-yl)piperazin-1-ylsulfonyl)benzonitrile68. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.20 (s, 1H), 7.85(d, J=8 Hz, 1H), 7.40 (m, 2H), 7.33 (d, J=7 Hz, 1H), 6.71 (d, J=9 Hz,1H), 3.23 (m, 4H), 2.54 (m, 3H), 2.46 (m, 2H), 2.31 (s, 3H), 2.23 (s,3H), 1.40 (m, 1H), 1.26 (m, 2H), 1.22 (m, 1H), 0.86 (m, 6H); MS (ESI,EI⁺): m/z=458 (MH⁺); melting point: 94-99° C.

4-(2,5-Dimethylphenylthio)-3-(4-(pentan-3-yl)piperazin-1-ylsulfonyl)benzonitrile,hydrochloride 68. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.77(s, 1H), 8.28 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=8Hz, 1H), 7.35 (d, J=8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 4.00 (m, 2H), 3.45(m, 5H), 3.15 (m, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.80 (m, 1H), 1.38(m, 2H), 1.24 (d, J=8 Hz, 4H), 0.90 (t, J₁=J₂=8 Hz, 3H); MS (ESI, EI⁺):m/z=458 (MH⁺); melting point: 200-202° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dimethylphenylthio)-benzonitrile69. HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.19 (d, J=2 Hz, 1H),7.85 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J=8 Hz, 1H),7.33 (d, J=8 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.25 (s, 4H), 2.48 (s, 4H),2.31 (s, 3H), 2.23 (s, 3H), 1.73 (m, 2H), 1.56 (m, 2H), 1.48 (m, 2H),1.29 (2H); MS (ESI, m/z=456 (MH⁺); melting point: 168-170° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dimethylphenylthio)-benzonitrile,hydrochloride 69. HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 11.25(s, 1H), 8.27 (d, J=2 Hz, 1H), 7.90 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.48 (s,1H), 7.41 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 6.74 (d, J=8 Hz, 1H),3.97 (m, 2H), 3.53 (m, 3H), 3.37 (m, 2H), 3.11 (m, 2H), 2.32 (s, 3H),2.24 (s, 3H), 1.99 (m, 2H), 1.74 (m, 4H), 1.54 (m, 2H); MS (ESI, EI⁺):m/z=456 (MH⁺).

4-(2,5-Dimethylphenylthio)-3-(4-methyl-1,4-diazepan-1-ylsulfonyl)benzonitrile70. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.23 (s, 1H), 7.82(d, J=7 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz,1H), 6.72 (d, J=9 Hz, 1H), 3.53 (m, 2H), 3.48 (t, J₁=J₂=6 Hz, 2H), 2.58(m, 4H), 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 1.84 (m, 2H); MS(ESI, EI⁺): m/z=416 (MH⁺).

4-(2,5-Dimethylphenylthio)-3-(morpholinosulfonyl)benzonitrile 71. HPLCpurity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.21 (s, 1H), 7.86 (d, J=9Hz, 1H), 7.45 (s, 1H), 7.40 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 6.71(d, J=8 Hz, 1H), 3.66 (m, 4H), 3.25 (m, 4H), 2.32 (s, 3H), 2.24 (s, 3H);MS (ESI, EI⁺): m/z=343 (MH⁺); melting point: 206-209° C.

5-Cyano-N-(2-(diethylamino)ethyl)-2-(2,5-dimethylphenylthio)-benzenesulfonamide,hydrochloride 73. HPLC purity: 97.3%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.29(s, 1H), 8.55 (t, J₁=J₂=6 Hz, 1H), 8.24 (d, J=2 Hz, 1H), 7.86 (dd, J₁=2Hz, J₂=8 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz,1H), 6.76 (d, J=8 Hz, 1H), 3.31 (m, 2H), 3.16 (m, 6H), 2.33 (s, 3H),2.22 (s, 3H), 1.21 (t, J₁=J₂=7 Hz, 6H); MS (ESI, EI⁺): m/z=418 (MH⁺);melting point: 181-184° C.

4-(2,5-Dimethylphenylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)-benzonitrile74. HPLC purity: 98.4%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.21 (d, J=2 Hz,1H), 7.84 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.42 (s, 1H), 7.40 (d, J=8 Hz,1H), 7.33 (d, J=8 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 3.68 (m, 2H), 2.95 (m,2H), 2.45 (s, 4H), 2.31 (s, 3H), 2.21 (s, 3H), 2.15 (m, 1H), 1.88 (m,2H), 1.65 (s, 4H), 1.47 (m, 2H); MS (ESI, EI⁺): m/z=457 (MH⁺); meltingpoint: 179-181° C.

4-(2,5-Dimethylphenylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)-benzonitrile,hydrochloride 74. HPLC purity: 98.1%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.98(s, 1H), 8.24 (d, J=2 Hz, 1H), 7.86 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.49 (s,1H), 7.40 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 6.71 (d, J=8 Hz, 1H),3.94 (m, 2H), 3.47 (m, 2H), 3.24 (m, 1H), 3.00 (m, 2H), 2.83 (t,J₁=J₂=12 Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.15 (m, 2H), 1.96 (m,2H), 1.85 (m, 2H), 1.76 (m, 2H); MS (ESI, EI⁺): m/z=456 (MH⁺).

4-(2,5-Dimethylphenylthio)-3-(thiomorpholinosulfonyl)benzonitrile 85.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.24 (d, J=1 Hz, 1H),7.85 (dd, J₁=7 Hz, J₂=1 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J=8 Hz, 1H),7.34 (d, J=8 Hz, 1H), 6.72 (d, J=8 Hz, 1H), 3.58 (m, 4H), 2.70 (m, 4H),2.32 (s, 3H), 2.22 (s, 3H); MS (ESI, EI⁺): m/z=343 (MH⁺); melting point:196-199° C.

Compound 86. HPLC purity: 97.8%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.31 (d,J=1 Hz, 1H), 7.88 (dd, J₁=7 Hz, J₂=1 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J=8Hz, 1H), 7.34 (d, J=8 Hz, 1H), 6.74 (d, J=8 Hz, 1H), 3.83 (m, 4H), 3.31(m, 4H), 2.32 (s, 3H), 2.22 (s, 3H); MS (ESI, EI⁺): m/z=500 (MH⁺);melting point: 169-173° C.

Example 3 Preparation of4-(2,5-dichlorophenylthio)-3-(4-(dimethylamino)piperidin-1-ylsulfonyl)benzonitrile

Compound 83 was synthesized as shown in Scheme 5.

4-(2,5-Dichlorophenylthio)-3-nitrobenzonitrile 27. To a solution of4-chloro-3-nitrobenzonitrile (10.0 g, 54.77 mmol) in THF (300 mL) wasadded 2,5-dichlorobenzenethiol (19.6 g, 12.108 mmol) and K₂CO₃ (37.8 g,273.85 mmol). The reaction mixture was refluxed for 48 hrs. The solidwas filtered and washed with copious amounts of EtOAc. The filtrate waswashed sequentially with saturated NaHCO₃, H₂O, and saturated NaClsolution, dried over MgSO₄, filtered, and evaporated in vacuo. Theresulting solid was then triturated with DCM and hexanes, and filteredto yield compound 27 as a yellow solid (11.823 g, 91.0% HPLC purity,66.4% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 8.82 (d, J=2 Hz, 1H), 8.00(m, 3H), 7.80 (d, J=9 Hz, 1H), 7.75 (dd, J₁=3 Hz, J₂=9 Hz, 1H), 6.97 (d,J=9 Hz, 2H).

3-Amino-4-(2,5-dichlorophenylthio)benzonitrile 28. A solution ofcompound 27 (11.8 g, 36.36 mmol) in THF (200 mL) was combined with asolution of sodium hydrosulfite (37.98 g, 218.16 mmol) in water (50 mL).The combined solution was stirred vigorously overnight at 45° C. Thereaction was monitored by TLC (25% EtOAc in hexanes), and was completeafter 16 hrs as indicated by absence of the starting material. Thereaction was removed from heat and THF was evaporated. Aqueous solutionwas filtered to yield a white solid. The solid was washed with water anddried in a vacuum oven overnight to yield compound 28 (9.077 g, 97% HPLCpurity, 84.6% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 7.55 (d, J=8 Hz, 1H),7.48 (d, J=8 Hz, 1H), 7.28 (dd, J₁=2 Hz, J₂=7 Hz, 1H), 7.19 (d, J=2 Hz,1H), 6.99 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.50 (d, J=2 Hz, 1H), 6.04 (s,2H).

5-Cyano-2-(2,5-dichlorophenylthio)benzene-1-sulfonyl chloride 29. Asolution of compound 28 (6.00 g, 20.34 mmol) in acetic acid (100 mL) wasadded HCl (12 M, 40.00 mL). The solution was stirred at 85° C. for 20min. The solution was then cooled to room temperature. A solution ofNaNO₂ (2.807 g, 40.68 mmol) in water (5 mL) was added dropwise to thecompound 28 containing solution stirred in an ice bath. After addition,the solution was stirred in an ice bath for additional 2 hrs. In aseparate flask, SO₂ was bubbled through acetic acid (100 mL) for 45 minat room temperature to form a SO₂ saturated solution. CuCl₂ (1.007 g,10.17 mmol) was then added to the SO₂ saturated solution and stirred foradditional 15 min to form a CuCl₂ solution. The CuCl₂ solution was thencooled with an ice bath and stirred for 10 min. The compound 28containing solution was then added dropwise into the CuCl₂ solution.After the addition, the solution was stirred for additional 45 min, andwas then poured onto ice water and stirred for 1 hr. The resultingprecipitate was then filtered to yield compound 29 as an orange solid(1.3 g, 80% HPLC purity, 17% yield).

4-(2,5-Dichlorophenylthio)-3-(4-(dimethylamino)piperidin-1-ylsulfonyl)benzonitrile83. To a solution of compound 29 (0.100 g, 0.26 mmol) in DCM (8.00 mL)was added 4-dimethylaminopiperidine (0.044 g, 0.34 mmol) and TEA (0.034g, 0.34 mmol). The reaction was monitored with TLC (25% EtOAc inhexanes, R_(f)=0.0). After stirring at room temperature for 2 hrs, thereaction was complete as indicated by the absence of the startingmaterial (TLC). Water was added and aqueous layer was extracted twicewith DCM. Combined extracts were washed sequentially with water andbrine, dried over MgSO₄, filtered, and evaporated in vacuo to form aclear oil. The oil was dissolved in DCM and purified with chromatographywith a gradient from 0 to 30% MeOH in DCM. Pure fractions were combined,evaporated in vacuo, triturated with DCM and hexanes, and then filteredto yield compound 83 as a white powder (0.068 g, 100% HPLC purity, 56%yield). ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz, 1H), 7.89 (m, 2H),7.78 (d, J=9 Hz, ¹H), 7.71 (dd, J₁=3 Hz, J₂=9 Hz, 1H), 6.93 (d, J=8 Hz,1H), 3.79 (d, J=12 Hz, 2H), 2.85 (t, J=13 Hz, 2H), 2.22 (m, 1H), 2.12(s, 6H), 1.79 (m, 2H), 1.40 (m, 2H); MS (ESI, EI⁺): m/z=470 (MH⁺);melting point: 140-143° C.

4-(2,5-Dichlorophenylthio)-3-(4-(dimethylamino)piperidin-1-ylsulfonyl)benzonitrile,hydrochloride 83. To a solution of neutral compound 83 (15.0 mg, 0.03mmol) in 1,4-dioxane (2.0 mL) was added 4 N HCl in 1,4-dioxane (30.0 μL,0.12 mmol). The reaction mixture was stirred for 10 min at roomtemperature before adding 2 mL of diethyl ether. A white precipitate wasformed and collected via filtration to obtain compound 83 hydrochlorideas a white solid as product (15.0 mg, 100% HPLC purity, 99% yield). HPLCpurity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.64 (s, 1H), 8.29 (d, J=2Hz, 1H), 7.94 (d, J=2 Hz, 1H), 7.91 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.79 (d,J=8 Hz, 1H), 7.72 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 3.97(d, J=12 Hz, 2H), 3.29 (m, 1H), 2.84 (t, J₁=J₂=12 Hz, 2H), 2.68 (d, J=8Hz, 6H), 2.12 (d, J=12 Hz, 2H), 1.69 (m, 2H); MS (ESI, EI⁺): m/z=470(MH⁺); melting point: 267-269° C.

The following compounds were made according to the procedures asdescribed in this example.

4-(2,5-Dichlorophenylthio)-3-(piperazin-1-yl sulfonyl)benzonitrile 76.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.24 (d, J=2 Hz, 1H),7.89 (m, 2H), 7.79 (d, J=8 Hz, 1H), 7.72 (dd, J₁=2 Hz, J₂=8 Hz, 1H),6.91 (d, J=8 Hz, 1H), 3.15 (m, 4H), 2.73 (m, 4H); MS (ESI, EI⁺): m/z=429(MH⁺); melting point: 190-194° C.

4-(2,5-Dichlorophenylthio)-3-(piperazin-1-ylsulfonyl)benzonitrile,dihydrochloride 76. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.30(s, 2H), 8.32 (d, J=2 Hz, 1H), 7.95 (m, 2H), 7.80 (d, J=8 Hz, 1H), 7.73(dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 3.54 (m, 4H), 3.19 (m,4H); MS (ESI, EI⁺): m/z=428 (MH⁺); melting point: 156-162° C.

4-(2,5-Dichlorophenylthio)-3-(4-isopropylpiperazin-1-ylsulfonyl)benzonitrile77. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.25 (d, J=2 Hz,1H), 7.91 (dd, J₁=2 Hz, J₂=8 Hz, 2H), 7.78 (d, J=8 Hz, 1H), 7.71 (dd,J₁=2 Hz, J₂=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 3.24 (m, 4H), 2.67 (m, 1H),2.48 (m, 4H), 0.92 (d, J=7 Hz, 6H); MS (ESI, EI⁺): m/z=472 (MH⁺);melting point: 163-166° C.

4-(2,5-Dichlorophenylthio)-3-(4-isopropylpiperazin-1-ylsulfonyl)benzonitrile,hydrochloride 77. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.77(s, 1H), 8.34 (d, J=2 Hz, 1H), 7.95 (m, 2H), 7.80 (d, J=8 Hz, 1H), 7.73(dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 3.99 (d, J=12 Hz, 2H),3.49 (m, 3H), 3.34 (m, 2H), 3.11 (m, 2H), 1.25 (d, J=8 Hz, 6H); MS (ESI,EI⁺): m/z=470 (MH⁺); melting point: 259-285° C.

4-(2,5-Dichlorophenylthio)-3-(4-(pentan-3-yl)piperazin-1-ylsulfonyl)-benzonitrile78. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz,1H), 7.90 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 7.79 (d, J=8Hz, 1H), 7.71 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 3.23 (m,4H), 2.51 (m, 4H), 2.15 (m, 1H), 1.36 (m, 2H), 1.21 (m, 2H), 0.81 (t,J₁=J₂=7 Hz, 6H); melting point: 127-130° C.

4-(2,5-Dichlorophenylthio)-3-(4-(pentan-3-yl)piperazin-1-ylsulfonyl)-benzonitrile,hydrochloride 78. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.62(s, 1H), 8.33 (d, J=2 Hz, 1H), 7.95 (m, 2H), 7.80 (d, J=8 Hz, 1H), 7.73(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 3.95 (d, J=13 Hz, 2H),3.48 (m, 4H), 3.07-3.18 (m, 3H), 1.81 (m, 2H), 1.60 (m, 2H), 0.85 (t,J₁=J₂=7 Hz, 6H); melting point: 239-248° C.

4-(2,5-Dichlorophenylthio)-3-(3,5-dimethylpiperazin-1-ylsulfonyl)benzonitrile79. HPLC purity: 97.2%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.25 (d, J=2 Hz,1H), 7.90 (d, J=2 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 7.79 (d, J=8 Hz, 1H),7.72 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.90 (d, J=7 Hz, 1H), 3.65 (m, 2H),2.72 (m, 2H), 2.20 (t, J₁=J₂=11 Hz, 3H); melting point: 176-180° C.

4-(2,5-Dichlorophenylthio)-3-(3,5-dimethylpiperazin-1-ylsulfonyl)benzonitrile,dihydrochloride 79. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.48(s, 1H), 9.10 (s, 1H), 8.32 (d, J=2 Hz, 1H), 7.96 (d, J=2 Hz, 1H), 7.93(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.74 (dd, J₁=2 Hz,J₂=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 3.99 (d, J=13 Hz, 2H), 3.37 (m, 2H),2.89 (t, J=12 Hz, 2H), 1.25 (d, J=7 Hz, 6H); MS (ESI, EI⁺): m/z=456(MH⁺); melting point: 160-190° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dichlorophenylthio)-benzonitrile80. HPLC purity: 99.6%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.24 (d, J=2 Hz,1H), 7.90 (m, 2H), 7.78 (d, J=8 Hz, 1H), 7.70 (dd, J₁=2 Hz, J₂=8 Hz,1H), 6.92 (d, J=8 Hz, 1H), 3.25 (m, 4H), 2.47 (m, 4H), 1.72 (m, 2H),1.56 (m, 2H), 1.47 (m, 2H), 1.27 (m, 2H); MS (ESI, EI⁺): m/z=496 (MH⁺);melting point: 198-200° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dichlorophenylthio)-benzonitrile,hydrochloride 80. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): 11.25(s, 1H), 8.33 (d, J=2 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.95 (dd, J₁=2 Hz,J₂=8 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 7.73 (dd, J₁=2 Hz, J₂=8 Hz, 1H),6.95 (d, J=8 Hz, 1H), 3.97 (d, J=13 Hz, 2H), 3.57 (m, 2H), 4.51 (m, 1H),3.35 (m, 2H), 3.09 (m, 2H), 1.97 (m, 2H), 1.69-1.78 (m, 4H), 1.53 (m,2H); MS (ESI, EI⁺): m/z=496 (MH⁺); melting point: 260-285° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dichlorophenylthio)-benzonitrile,sulfuric acid 80. HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.48(s, 1H), 8.34 (d, J=2 Hz, 1H), 7.95 (m, 2H), 7.81 (d, J=8 Hz, 1H), 7.74(dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 4.00 (m, 2H), 3.59 (m,4H), 3.13 (m, 4H), 2.00 (m, 2H), 1.53-1.72 (m, 6H); melting point:230-240° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dichlorophenylthio)-benzonitrile, ethanesulfonic acid80. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.65 (s, 1H), 8.34(d, J=2 Hz, 1H), 7.95 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 1H), 7.74 (dd,J₁=2 Hz, J₂=8 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 4.00 (m, 2H), 3.57 (m, 3H),3.14 (m, 4H), 2.40 (dd, J₁=J₂=7 Hz, 3H), 1.99 (m, 2H), 1.67 (m, 3H),1.54 (m, 2H), 1.04 (t, J₁=J₂=7 Hz, 3H); melting point: 63-65° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dichlorophenylthio)-benzonitrile,nitric acid 80. HPLC purity: 97.8%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.44(s, 1H), 8.34 (d, J=2 Hz, 1H), 7.95 (m, 2H), 7.81 (d, J=8 Hz, 1H), 7.74(dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 4.01 (d, J=10 Hz, 2H),3.60 (d, J=10 Hz, 2H), 3.05-3.17 (m, 4H), 2.00 (m, 2H), 1.54-1.69 (m,7H); melting point: 170-190° C.

3-(4-Cyclopentylpiperazin-1-ylsulfonyl)-4-(2,5-dichlorophenylthio)-benzonitrile,oxalic acid 80. HPLC purity: 98%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.29 (s,1H), 7.93 (m, 2H), 7.79 (d, J=8 Hz, 1H), 7.72 (dd, J₁=2 Hz, J₂=8 Hz,1H), 6.94 (d, J=8 Hz, 1H), 3.42 (s, 4H), 3.01 (m, 1H), 2.91 (s, 4H),1.85 (m, 2H), 1.62 (m, 2H), 1.50 (m, 4H).

4-(2,5-Dichlorophenylthio)-3-(4-methyl-1,4-diazepan-1-ylsulfonyl)-benzonitrile81. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz,1H), 7.88 (m, 2H), 7.76 (d, J=8 Hz, 1H), 7.70 (dd, J₁=2 Hz, J₂=8 Hz,1H), 6.95 (d, J=8 Hz, 1H), 3.54 (m, 2H), 3.48 (t, J₁=J₂=6 Hz), 2.58 (m,2H), 2.54 (m, 2H), 2.26 (s, 3H), 1.81 (m, 2H); MS (ESI, EI⁺): m/z=456(MH⁺); melting point: 101-104° C.

4-(2,5-Dichlorophenylthio)-3-(4-methyl-1,4-diazepan-1-ylsulfonyl)-benzonitrile,hydrochloride 81. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 10.68(s, 1H), 8.31 (d, J=2 Hz, 1H), 7.91 (m, 2H), 7.78 (d, J=8 Hz, 1H), 7.71(dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 4.01 (m, 1H), 3.67 (m,1H), 3.48-3.59 (m, 4H), 3.23 (m, 2H), 2.81 (s, 3H), 2.16 (m, 2H); MS(ESI, EI⁺): m/z=456 (MH⁺); melting point: 241-255° C.

4-(2,5-Dichlorophenylthio)-3-(morpholinosulfonyl)benzonitrile 82. HPLCpurity: 96%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz, 1H), 7.96 (d,J=2 Hz, 1H), 7.91 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 7.72(dd, J₁=2 Hz, J₂=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 3.65 (m, 4H), 3.26 (m,4H); melting point: 216-219° C.

4-(2,5-Dichlorophenylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)benzonitrile84. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz,1H), 7.89 (m, 2H), 7.79 (d, J=8 Hz, 1H), 7.70 (dd, J₁=2 Hz, J₂=8 Hz,1H), 6.92 (d, J=8 Hz, 1H), 3.67 (m, 2H), 2.96 (m, 2H), 2.43 (m, 4H),2.12 (m, 1H), 1.85 (m, 2H), 1.64 (m, 4H), 1.47 (m, 2H); MS (ESI, EI⁺):m/z=496 (MH⁺); melting point: 177-180° C.

4-(2,5-Dichlorophenylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)benzonitrile,hydrochloride 84. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): 10.88(s, 1H), 8.29 (d, J=2 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.91 (dd, J₁=2 Hz,J₂=8 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 7.71 (dd, J₁=2 Hz, J₂=8 Hz, 1H),6.93 (d, J=8 Hz, 1H), 3.94 (d, J=13 Hz, 2H), 3.45 (m, 2H), 3.23 (m, 1H),3.00 (m, 2H), 2.82 (t, J₁=J₂=12 Hz, 2H), 2.14 (d, J=12 Hz, 2H), 1.93 (m,2H), 1.85 (m, 2H), 1.74 (m, 2H); MS (ESI, EI⁺): m/z=496 (MH⁺); meltingpoint: 285-300° C.

Methyl4-(5-cyano-2-(2,5-dichlorophenylthio)phenylsulfonyl)piperazine-2-carboxylate138. HPLC purity: 99.3%; ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J=2 Hz, 1H),7.70 (d, J=2 Hz, 1H), 7.55 (dd, J₁=8 Hz, J₂=2 Hz, 1H), 7.54 (d, J=9 Hz,1H), 7.47 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 6.83 (d, J=8 Hz, 1H), 4.04 (m,2H), 3.73 (m, 1H), 3.61 (m, 3H), 3.18 (m, 1H), 1.13 (d, J=6 Hz, 3H); MS(ESI, EI⁺): m/z=486 (MH⁺); melting point: 124-136° C.

Example 4 Preparation of4-(2,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)benzonitrile

Compound 51 was synthesized as shown in Scheme 6.

4-(2,5-Dimethylphenoxy)-3-nitrobenzonitrile 30. 2,5-Dimethylphenol (6.99g, 57.20 mmol) and 4-chloro-3-nitrobenzonitrile (8.00 g, 43.96 mmol)were combined with K₂CO₃ (30.40 g, 220.00 mmol) in THF (100 mL). Thereaction mixture was heated to reflux for 48 hrs and then the solid wasfiltered through a bed of Celite. After rinsing the residue with copiousamounts of EtOAc, the filtrate was washed sequentially with NaHCO₃,water, and brine, dried over anhydrous MgSO₄, and filtrated. Thefiltrate was concentrated in vacuo to produce compound 30 as a whitepowder (10.00 g, 85.0% yield, 99.1% pure). ¹H NMR (500 MHz, DMSO-d₆): δ8.65 (d, J=2 Hz, 1H), 8.03 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.28 (d, J=8 Hz,1H), 7.09 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=9 Hz, 1H), 2.28 (s,3H), 2.07 (s, 3H).

3-Amino-4-(2,5-dimethylphenoxy)benzonitrile 31. The coupled product 30(12.00 g, 44.73 mmol) was reduced with sodium hydrosulfite (30.47 g,175.00 mmol) in a mixture of THF (75 mL), water (100 mL), and dioxane(45 mL). After the reaction is complete, volatile organic solvents wereremoved in vacuo and the precipitate in the remaining water wascollected via vacuum filtration to afford compound 31 as a white solid(9.50 g, 89.0% yield, 99.5% pure). ¹H NMR (500 MHz, DMSO-d₆): δ 7.19 (d,J=8 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 6.86 (dd, J₁=8Hz, J₂=2 Hz, 1H), 6.74 (s, 1H), 6.45 (d, J=8 Hz, 1H), 5.52 (s, 2H), 2.23(s, 3H), 2.08 (s, 3H).

5-Cyano-2-(2,5-dimethylphenoxy)benzene-1-sulfonyl chloride 32. Forconversion from aniline 31 to sulfonyl chloride 32, the Sandmeyerreaction is utilized. Aniline 31 (9.00 g) was dissolved in acetic acid(100 mL). HCl (80 mL) (12 M) was added. Separately, sodium nitrite (5.33g, 77.20 mmol) was dissolved in minimal water and slowly infused intothe HCl salt solution. The resulting reaction mixture was stirred for 2hrs in an ice bath.

In another reaction vessel, 100 mL of acetic acid is saturated with SO₂gas. Copper (II) chloride (1.91 g, 19.30 mmol) was added. After the aquacolor changes to olive green, the CuCl₂ solution was cooled with an icebath and the sodium nitrite solution was slowly added to the CuCl₂solution. After stirring for another 45 min, the mixture was poured intoice water and stirred for 1 hr. The resulting precipitate was collectedvia filtration to afford compound 32 as an orange solid (9.50 g, 76.0%yield).

Tert-butyl4-(5-cyano-2-(2,5-dimethylphenoxy)phenylsulfonyl)piperazine-1-carboxylate33. A solution of sulfonyl chloride 32 (0.160 g, 0.50 mmol), tert-butylpiperazine-1-carboxylate (0.121 g, 0.65 mmol), and TEA (0.066 g, 0.65mmol) in DCM (5 mL) was stirred overnight at room temperature. Thereaction was monitored with TLC (25% EtOAc in hexanes). The reactionmixture was concentrated in vacuo and the residual was redissolved witha minimal amount of DCM and chromatographed on normal-phase silica toproduce compound 33 as a white powder (0.099 g, 42.0% yield, 100.0%pure). ¹H NMR (500 MHz, DMSO-d₆): δ 8.24 (d, J=2 Hz, 1H), 8.00 (dd, J₁=2Hz, J₂=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.98 (s,1H), 6.78 (d, J=8 Hz, 1H), 3.39 (m, 4H), 3.22 (m, 4H), 2.29 (s, 3H),2.07 (s, 3H), 1.37 (s, 9H); MS (ESI, EI⁺): m/z=372 (MH⁺).

4-(2,5-Dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)benzonitrile 51. Asolution of sulfonyl chloride 32 (1.0 g, 3.1 mmol) in 20 mLdichloromethane was infused into a stirring solution of piperazine (5.9g, 62.2 mmol) in 20 mL of dichloromethane at a rate of 0.2 mL/min. Thereaction mixture was stirred for 16 hrs. The completion of the reactionwas confirmed by TLC (25% EtOAc in hexanes). Water was then added andthe aqueous layer was extracted twice with dichloromethane. The combinedorganic layers were washed sequentially with water and brine, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo to produce a brownsolid. The product was chromatographed on normal-phase silica using agradient of 0-25% MeOH in dichloromethane. Desired fractions werecollected and concentrated to produce compound 51 as a pink solid (0.5g, 1.3 mmol). HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.22 (d,J=2 Hz, 1H), 7.99 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.09(d, J=8 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J=8 Hz, 1H), 3.13 (m, 4H), 2.70(m, 4H), 2.30 (s, 3H), 2.08 (s, 3H); MS (ESI, EI⁺): m/z=372 (MH⁺);melting point: 60-72° C.

4-(2,5-Dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)benzonitrile,dihydrochloride 51. To a solution of neutral compound 51 (0.1 g 0.27mmol) in 3 mL of 1,4-dioxane was added 4 N HCl in 1,4-dioxane (0.270mL). The reaction mixture was stirred at room temperature overnight anddiethyl ether (3 mL) was added and stirred for 30 min. Another 2 mL ofdiethyl ether was added. An oil began to form. The solvents were removedunder vacuum. Hexanes (3 mL) were added to the resulting residue and themixture was sonicated. Ethyl acetate (2-3 drops) was added andprecipitate began to form in the oil. The resulting white-yellow powderwas collected to yield compound 51 dihydrochloride. HPLC purity: 99.8%;¹H NMR (500 MHz, DMSO-d₆): δ 9.23 (s, 2H), 8.28 (d, J=2 Hz, 1H), 8.04(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H),7.06 (s, 1H), 6.78 (d, J=8 Hz, 1H), 3.52 (m, 4H), 3.18 (m, 4H), 2.31 (s,3H), 2.08 (s, 3H); MS (ESI, EI⁺): m/z=372 (MH⁺); melting point: 120-195°C.

Example 5 Preparation of4-(2,5-dichlorophenoxy)-3-(4-methylpiperidin-1-ylsulfonyl)benzonitrile

Compound 87 was synthesized as shown in Scheme 7.

4-(2,5-Dichlorophenoxy)-3-nitrobenzonitrile 34. 2,5-Dichlorophenol(17.86 g, 109.54 mmol) and 4-chloro-3-nitrobenzonitrile (10.00 g, 54.77mmol) were combined with K₂CO₃ (37.85 g, 273.85 mmol) in THF (300 mL).The reaction mixture was refluxed for 48 hrs and then the solid wasfiltered over a bed of Celite. After rinsing the residue with copiousamounts of DCM, the filtrate was concentrated to produce a yellow solid.The solid was triturated with minimal DCM and collected via vacuumfiltration to yield compound 34 (13.84 g, 81.7% yield, 100.0% pure). ¹HNMR (500 MHz, DMSO-d₆): δ 8.73 (s, 1H), 8.12 (dd, J₁=9 Hz, J₂=2 Hz, 1H),7.73 (d, J=9 Hz, 1H), 7.65 (d, J=2 Hz, 1H), 7.48 (dd, J₁=9 Hz, J₂=2 Hz,1H), 7.21 (d, J=9 Hz, 1H).

3-Amino-4-(2,5-dichlorophenoxy)benzonitrile 35. The coupled product 34was reduced with sodium hydrosulfite ((49.76 g, 268.56 mmol) in amixture of THF (200 mL) and water (100 mL). After the reaction wascomplete, THF was removed in vacuo. The product was precipitated outfrom the remaining reaction mixture, and was collected via vacuumfiltration to yield compound 35 (12.961 g, 103.7% yield, 97.3% pure). ¹HNMR (500 MHz, DMSO-d₆): δ 7.64 (d, J=9 Hz, 1H), 7.31 (dd, J₁=9 Hz, J₂=2Hz, 1H), 7.13 (d, J=2 Hz, 1H), 7.08 (d, J=2 Hz, 1H), 6.93 (dd, J₁=8 Hz,J₂=2 Hz, 1H), 6.74 (d, J=8 Hz, 1H), 5.63 (s, 2H).

5-Cyano-2-(2,5-dichlorophenoxy)benzene-1-sulfonyl chloride 36. Forconversion from aniline 35 to sulfonyl chloride 36, the Sandmeyerreaction was utilized. Aniline 35 (5.00 g, 17.91 mmol) was suspended ina mixture of water (20 mL) and conc. HCl (20 mL). The mixture waschilled to 0° C. in an ice bath and an aqueous solution of sodiumnitrite (1.85 g, 26.87 mmol) was slowly added, resulting in anorange-white suspension. After addition of sodium nitrite, the mixturewas stirred at 0° C. for 1 hr. Separately, 100 mL of acetic acid wassaturated with SO₂ gas. After 45 minutes of bubbling, copper (II)chloride dihydrate (1.53 g, 8.96 mmol) was added, and the acetic acidsolution was stirred until the bright aqua green of the copper turnedinto a brownish olive green color. The CuCl₂ solution was chilled to 0°C., and then the sodium nitrite solution was slowly added to it and leftto stir for another hour. An Erlenmeyer flask was filled with crushedice and enough water to cover the ice. It was agitated on a shaker andthe combined solutions were carefully added. The solid product wasprecipitated out into the ice water and the suspension was agitateduntil the ice melted. The product 36 as a light pink powder wascollected via vacuum filtration (2.363 g, 36.4% yield). ¹H NMR (500 MHz,DMSO-d₆): δ 8.11 (d, J=2 Hz, 1H), 7.80 (dd, J₁=8 Hz, J₂=2 Hz, 1H), 7.64(d, J=9 Hz, 1H), 7.30 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 6.99 (d, J=2 Hz, 1H),6.95 (d, J=8 Hz, 1H).

4-(2,5-Dichlorophenoxy)-3-(4-methylpiperidin-1-ylsulfonyl)benzonitrile87. Sulfonyl chloride 36 (0.20 g, 0.55 mmol) was combined with4-methylpiperidine (0.16 g, 1.65 mmol) and TEA (0.17 g, 1.65 mmol) inDCM (5 mL). The solution was stirred overnight at room temperature. Uponconsumption of starting material, as determined via TLC (75% EtOAc inhexanes), the reaction mixture was partitioned between DCM and water.After 3 extractions, the combined organic extracts were washedsequentially with saturated aqueous NaHCO₃, water, and brine. The crudeproduct was chromatographed on normal-phase silica to yield the desiredproduct 87 (0.167 g, 71.4% yield, 97.1% pure). ¹H NMR (500 MHz,DMSO-d₆): δ 8.28 (d, J=2 Hz, 1H), 8.07 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.72(d, J=8 Hz, 1H), 7.46 (dd, J₁=5 Hz, J₂=2 Hz, 1H), 7.44 (d, J=2 Hz, 1H),7.10 (d, J=9 Hz, 1H), 3.70 (d, J=12 Hz, 2H), 2.74 (ddd, J₁=J₂=12 Hz,J3=2 Hz, 2H), 1.65 (dd, J₁=13 Hz, J₂=2 Hz, 2H), 1.44 (m, 1H), 1.09 (ddd,J₁=28 Hz, J₂=13 Hz, J₃=4 Hz, 2H), 0.87 (d, J=7 Hz, 3H); MS (ESI, EI⁺):m/z=425.11 (MH⁺); melting point: 127-130° C.

The following compounds were made according to the procedures asdescribed in this example.

4-(2,5-Dichlorophenoxy)-3-(4-isopropylpiperazin-1-ylsulfonyl)benzonitrile88. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz,1H), 8.09 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.48 (d, J=2Hz, 1H), 7.45 (dd, J₁=7 Hz, J₂=2 Hz, 1H), 7.13 (d, J=9 Hz, 1H), 3.02 (m,4H), 2.66 (quintuplet, J=7 Hz, 1H), 2.45 (m, 4H), 0.92 (d, J=7 Hz, 6H);MS (ESI, EI⁺): m/z=454.14 (MH⁺); melting point: 186-192° C.

4-(2,5-Dichlorophenoxy)-3-(4-(pentan-3-yl)piperazin-1-ylsulfonyl)-benzonitrile89. HPLC purity: 98.4%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz,1H), 8.09 (dd, J=9 Hz, J₂=2 Hz, 1H), 7.73 (dd, J₁=5 Hz, J₂=4 Hz, 1H),7.45 (m, 2H), 7.14 (d, J=9 Hz, 1H), 3.18 (m, 4H), 2.47 (m, 4H), 2.15(quintuplet, J=7 Hz, 1H), 1.36 (m, 2H), 1.21 (m, 2H), 0.81 (t, 6H); MS(ESI, EI⁺): m/z=482.12 (MH⁺); melting point: 138-141° C.

4-(2,5-Dichlorophenoxy)-3-(4-(pentan-2-yl)piperazin-1-ylsulfonyl)-benzonitrile90. HPLC purity: 98.5%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz,1H), 8.09 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.46 (dd,J₁=4 Hz, J₂=2 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 3.19(m, 4H), 2.53 (m, 1H), 2.40 (m, 2H), 1.38 (m, 1H), 1.24 (m, 2H), 1.16(m, 1H), 0.85 (d, J=6 Hz, 3H), 0.82 (d, J=7 Hz, 3H); MS (ESI, EI⁺):m/z=482.1 (MH⁺); melting point: 140-145° C.

3-(4-Cycloheptylpiperazin-1-ylsulfonyl)-4-(2,5-dichlorophenoxy)benzonitrile91. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.27 (d, J=2 Hz,1H), 8.09 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.47 (d, J=2Hz, 1H), 7.44 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 3.18 (m,4H), 2.47 (m, 4H), 1.42 (m, 13H); MS (ESI, EI⁺): m/z=508.15 (MH⁺);melting point: 179-183° C.

4-(2,5-Dichlorophenoxy)-3-(4-methyl-1,4-diazepan-1-ylsulfonyl)benzonitrile92. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz,1H), 8.09 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.50 (d, J=2Hz, 1H), 7.45 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.12 (d, J=9 Hz, 1H), 3.23 (m,5H), 2.33 (m, 5H), 2.16 (s, 3H); MS (ESI, EI⁺): m/z=426.15 (MH⁺);melting point: 169-173° C.

3-(4-(5-Butyl-7-chloro-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)piperidin-1-ylsulfonyl)-4-(2,5-dichlorophenoxy)benzonitrile93. HPLC purity: 99.8%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.30 (d, J=2 Hz,1H), 8.08 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.74 (d, J=9 Hz, 1H), 7.61 (d, J=2Hz, 1H), 7.47 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 4.43 (s,2H), 3.91 (m, 1H), 3.84 (d, J=12 Hz, 2H), 2.95 (dd, J₁=12 Hz, J₂=11 Hz,2H), 2.81 (t, J=8 Hz, 2H), 1.85 (d, J=10 Hz, 2H), 1.78 (ddd, J₁=25 Hz,J₂=12 Hz, J₃=4 Hz, 2H), 1.62 (quintuplet, J=7 Hz, 2H), 1.31 (quintuplet,J=7 Hz, 2H), 0.87 (t, J=7 Hz, 3H); MS (ESI, EI⁺): m/z=624.08 (MH⁺);melting point: 213-218° C.

4-(2,5-Dichlorophenoxy)-3-(piperazin-1-ylsulfonyl)benzonitrile,dihydrochloride 94. ¹H NMR (500 MHz, DMSO-d₆): δ 9.39 (s, 2H), 8.61 (d,J=2 Hz, 1H), 8.45 (dd, J₁=3 Hz, J₂=9 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 7.73(d, J=2 Hz, 1H), 7.53 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H),3.57 (m, 4H), 3.16 (m, 4H).

5-Cyano-2-(2,5-dichlorophenoxy)-N-(2-morpholinoethyl)benzenesulfonamide95. HPLC purity: 98.3%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.26 (d, J=2 Hz,1H), 8.02 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.87 (t, J=6 Hz, 1H), 7.74 (d, J=8Hz, 1H), 7.49 (dd, J₁=12 Hz, J₂=2 Hz, 1H), 7.47 (s, 1H), 6.99 (d, J=9Hz, 1H), 3.46 (t, J=4 Hz, 4H), 3.09 (quadruplet, J=6 Hz, 2H), 2.36 (t,J=6 Hz, 2H), 2.28 (s, 4H); MS (ESI, EI⁺): m/z=456 (MH⁺); melting point:164-167° C.

4-(2,5-Dichlorophenoxy)-3-(4-methylpiperazin-1-ylsulfonyl)benzonitrile96. HPLC purity: 99.8%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz,1H), 8.09 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.50 (d, J=2Hz, 1H), 7.45 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.12 (d, J=9 Hz, 1H), 3.23 (m,4H), 2.34 (m, 4H), 2.16 (s, 3H); MS (ESI EI⁺): m/z=467 (MH⁺); meltingpoint: 168-172° C.

4-(2,5-Dichlorophenoxy)-3-(4-(2-hydroxypropan-2-yl)piperidin-1-ylsulfonyl)benzonitrile97. HPLC purity: 99.4%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2 Hz,1H), 8.07 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.47 (d, J=2Hz, 1H), 7.45 (dd, J₁=8 Hz, J₂=2 Hz, 1H), 7.11 (d, J=9 Hz, 1H), 4.17 (s,1H), 3.80 (d, J=12 Hz, 2H), 2.68 (t. J=12 Hz, 2H), 1.75 (d, J=12 Hz,2H), 1.25 (m, 1H), 1.18 (m, 2H), 0.99 (s, 6H); MS (ESI, EI⁺): m/z=451(MH⁺); melting point: 95-100° C.

4-(2,5-Dichlorophenoxy)-3-(4-isopropyl-1,4-diazepan-1-ylsulfonyl)benzonitrile,hydrochloride 98. HPLC purity: 99.6%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.29(d, J=2 Hz, 1H), 7.74 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.47 (d, J=9 Hz, 1H),7.30 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.25 (d, J=2 Hz, 1H), 6.74 (d, J=9 Hz,1H), 4.02 (m, 2H), 3.77 (m, 1H), 3.55 (m, 1H), 3.45 (m, 1H), 3.38 (m,2H), 3.16 (m, 2H), 2.95 (m, 1H), 2.21 (m, 1H), 1.44 (dd, J₁=22 Hz, J₂=7Hz, 6H); MS (ESI, EI⁺): m/z=469 (MH⁺); melting point: 221-225° C.

Example 6 Preparation of1-(2-(2,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine

Compound 147 was synthesized as shown in Scheme 8.

2-Chloro-5-nitrobenzene-1-sulfonyl chloride 37. To an ice-bath chilledsolution of conc. HCl (100 mL) was added 2-chloro-5-nitroaniline (10 g)portion-wise. When complete dissolution was achieved, an aqueoussolution of sodium nitrite (6.0 g in 50 mL water) was added dropwise andthe resulting reaction mixture was stirred at 0° C. for 1 hr. The aboveobtained diazonium ion solution was then carefully added to an ice-bathchilled mixture of cupric chloride dihydrate (5 g) in acetic acid (500mL) pre-saturated with sulfur dioxide gas. After stirring the resultingreaction mixture at 0° C. for 1 hr, it was carefully added portion-wiseto an ice-water slurry with vigorous stirring. The separated solids werecollected by suction, rinsed with water, and dried under vacuum tofurnish the desired product 37 as a cream colored powder (8.2 g, 55%).¹H NMR (500 MHz, DMSO-d_(o)): δ 8.61 (d, J=3 Hz, 1H), 8.16 (dd, J₁=9 Hz,J₂=3 Hz, 1H), 7.70 (d, J=9 Hz, 1H).

Tert-butyl 4-(2-chloro-5-nitrophenylsulfonyl)piperazine-1-carboxylate38. A solution of compound 37 (0.600 g, 2.34 mmol) in DCM (20.00 mL) wasadded tort-butyl 1-piperazinecarboxylate (0.566 g, 3.04 mmol) and TEA(0.422 mL, 3.04 mmol). The reaction was monitored with TLC (25% EtOAc inhexanes, R_(f)=0.53). The reaction mixture was complete after stirringat room temperature for 1 hr, as indicated by the absence of thestarting material (TLC). Water was added and aqueous layer was extractedtwice with DCM. Combined extracts were sequentially washed with waterand brine, dried over MgSO₄, filtered, and evaporated in vacuo to afforda yellow solid. The solid was triturated with DCM and hexanes, and thenfiltered to yield compound 38 as a yellow solid (0.789 g, 100% HPLCpurity, 83% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 8.60 (d, J=3 Hz, 1H),8.47 (dd, J₁=3 Hz, J₂=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H), 3.37 (m, 4H),3.23 (m, 4H), 1.37 (s, 9H).

Tert-butyl4-(2-(2,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine-1-carboxylate39. To a solution of 2,5-dichlorophenol (0.414 g, 2.54 mmol) in THF(20.00 mL) stirred in an ice bath was added NaH (0.101 g, 2.54 mmol)slowly. After addition, the mixture was stirred for 5 min. Compound 38(0.790 g, 1.95 mmol) was then added and the resulting reaction mixturewas heated to 75° C. overnight. The reaction was monitored by HPLC.However, the reaction was not complete after 16 hrs (HPLC), so THF wasevaporated and 18-crown-6 (1.057 g, 4.00 mmol), DMF (15 mL), and K₂CO₃(0.553 g, 4.00 mmol) were added. The reaction mixture was heated to 100°C. for another 16 hrs, at which time HPLC indicated that the reactionwas complete by absence of starting material. The reaction mixture wascooled to room temperature, and water (0.250 mL) was added. The reactionmixture was extracted thrice with EtOAc. Combined extracts were washedsequentially with 1N NaOH, water, and brine, dried over MgSO₄, filtered,and evaporated in vacuo. The residual was dissolved in a minimal amountof DCM and purified with chromatography using a gradient of 5 to 30%EtOAc in hexanes. Pure fractions were combined and evaporated in vacuo.The resulting solid was triturated with DCM and hexanes, and thenfiltered to afford compound 39 as a white/yellow powder (0.120 g, 100%HPLC purity, 10.0% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 8.59 (d, J=2 Hz,1H), 8.42 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.66 (d, J=3Hz, 1H), 7.50 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 3.40 (m,4H), 3.25 (m, 4H), 1.37 (s, 9H).

1-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine 147. To asolution of compound 39 (0.100 g, 0.19 mmol) in DCM (6.00 mL) was added1N HCl in 1,4-dioxane (0.570 mL). The reaction was monitored with TLC(25% EtOAc in hexanes, R_(f)=0.0). The reaction was complete afterstirring at room temperature for 16 hrs, as indicated by the absence ofthe starting material). The reaction mixture was concentrated and theresidual was redissolved in MeOH (2.00 mL). Et₂O (4.00 mL) was thenadded and the mixture was stirred until precipitate formed (10 min). Thesolid was collected by filtration to yield compound 147 as a white solid(0.080 g, 100% HPLC purity, 83% yield). ¹H NMR (500 MHz, DMSO-d₆): δ9.39 (s, 2H), 8.61 (d, J=2 Hz, 1H), 8.45 (dd, J₁=3 Hz, J₂=9 Hz, 1H),7.78 (d, J=9 Hz, 1H), 7.73 (d, J=2 Hz, 1H), 7.53 (dd, J₁=2 Hz, J₂=8 Hz,1H), 7.12 (d, J=8 Hz, 1H), 3.57 (m, 4H), 3.16 (m, 4H).

1-(2-(2,5-Chlorophenoxy)-5-nitrophenylsulfonyl)piperazine, hydrochloride147. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.95 (s, 1H), 8.61(d, J=2 Hz, 1H), 8.46 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H),7.62 (d, J=2 Hz, 1H), 7.53 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.14 (d, J=8 Hz,1H), 3.52 (m, 4H), 3.20 (m, 4H); melting point: 224-227° C.

1-(2-(2,5-Chlorophenoxy)-5-nitrophenylsulfonyl)piperazine,dihydrochloride 147. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ9.39 (s, 2H), 8.61 (d, J=2 Hz, 1H), 8.45 (dd, J₁=3 Hz, J₂=9 Hz, 1H),7.78 (d, J=9 Hz, 1H), 7.73 (d, J=2 Hz, 1H), 7.53 (dd, J₁=2 Hz, J₂=8 Hz,1H), 7.12 (d, J=8 Hz, 1H), 3.57 (m, 4H), 3.16 (m, 4H).

The following compounds were made according to the procedures asdescribed in this example.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)-4-(pyrrolidin-1-yl)piperidine75. HPLC purity: 100%; ¹H NMR (500 MHz, CDCl₃) δ 8.77 (d, J=3 Hz, 1H),8.02 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J=8 Hz, 1H),7.27 (m, 1H), 6.78 (d, J=9 Hz, 1H), 3.87 (m, 2H), 3.00 (m, 2H), 2.55 (s,4H), 2.36 (s, 3H), 2.29 (s, 3H), 2.16 (m, 1H), 1.97 (m, 2H), 1.78 (m,4H), 1.68 (m, 2H); MS (ESI, EI⁺): m/z=476 (MH⁺); melting point: 184-188°C.

1-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)-4-ethylpiperazine 100.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.58 (d, J=2 Hz, 1H),8.43 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.59 (d, J=2 Hz,1H), 7.49 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 3.26 (m,4H), 2.40 (m, 4H), 2.33 (m, 2H), 0.95 (t, J₁=J₂=7 Hz, 3H); meltingpoint: 152-155° C.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)-4-ethylpiperazine101. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.50 (d, J=2 Hz,1H), 8.25 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=8 Hz,1H), 7.35 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 3.28 (s, 4H), 2.45 (s,4H), 2.35 (m, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 0.97 (t, J₁=J₂=7 Hz, 3H);melting point: 120-123° C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)-4-ethylpiperazine 102.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.58 (d, J=2 Hz, 1H),8.40 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz,1H), 7.00 (s, 1H), 6.85 (d, J=8 Hz, 1H), 3.27 (s, 4H), 2.41 (s, 4H),2.36 (m, 2H), 2.30 (s, 3H), 2.09 (s, 3H), 0.96 (t, J₁=J₂=7 Hz, 3H);melting point: 105-111° C.

1-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)-3,5-dimethylpiperazine103. HPLC purity: 95%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.49 (d, J=2 Hz,1H), 8.26 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.94 (d, J=2 Hz, 1H), 7.80 (d, J=8Hz, 1H), 7.73 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 3.63 (m,2H), 2.74 (m, 2H), 2.25 (t, J₁=J₂=7 Hz, 3H), 0.94 (d, J=8 Hz, 6H);melting point: 169-171° C.

1-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)-3,5-dimethylpiperazine104. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.58 (d, J=2 Hz,1H), 8.44 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.48 (m,2H), 7.18 (d, J=8 Hz, 1H), 3.57 (m, 2H), 2.70 (m, 2H), 2.25 (m, 3H),0.92 (d, J=8 Hz, 6H); melting point: 161-163° C.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)-3,5-dimethylpiperazine105. HPLC purity: 99.7%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.49 (d, J=2 Hz,1H), 8.24 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.42 (m, 2H), 7.35 (d, J=8 Hz,1H), 6.80 (d, J=8 Hz, 1H), 3.63 (m, 2H), 2.75 (m, 2H), 2.33 (s, 3H),2.27 (m, 2H), 2.23 (s, 3H), 0.95 (d, J=8 Hz, 6H); melting point:156-159° C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)-3,5-dimethylpiperazine106. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.57 (d, J=2 Hz,1H), 8.40 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.10 (d, J=8Hz, 1H), 6.94 (s, 1H), 6.84 (d, J=8 Hz, 1H), 3.58 (m, 2H), 2.72 (m, 2H),2.30 (s, 3H), 2.26 (m, 2H), 2.10 (s, 3H), 0.92 (d, J=8 Hz, 6H); meltingpoint: 148-151° C.

1-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)-4-isopropylpiperazine107. HPLC purity: 98.8%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.58 (d, J=3 Hz,1H), 8.43 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.57 (d, J=2Hz, 1H), 7.49 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.16 (d, J=9 Hz, 1H), 3.23 (t,J=4 Hz, 4H), 2.67 (m, 1H), 2.47 (t, J=5 Hz, 4H), 0.92 (d, J=7 Hz, 6H);MS (ESI, EI⁺): m/z=474 (MH⁺); melting point: 160-166° C.

1-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)-4-isopropylpiperazine108. HPLC purity: 99.3%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.75 (d, J=2 Hz,1H), 8.11 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.71 (d, J=2 Hz, 1H), 7.55 (d, J=9Hz, 1H), 7.48 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 6.85 (d, J=9 Hz, 1H), 3.39 (m,4H), 2.73 (m, 1H), 2.63 (m, 4H), 1.03 (d, J=7 Hz, 6H); MS (ESI, EI⁺):m/z=490 (MH⁺); melting point: 129-134° C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)-4-isopropylpiperazine109. HPLC purity: 99.7%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.86 (d, J=3 Hz,1H), 8.23 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.05 (d, J=7Hz, 1H), 6.85 (s, 1H), 6.72 (d, J=9 Hz, 1H), 3.41 (t, J=5 Hz, 4H), 2.73(m, 1H), 2.60 (t, J=5 Hz, 4H), 2.34 (s, 3H), 2.15 (s, 3H), 1.03 (d, J=7Hz, 6H); MS (ESI, EI⁺): m/z=434 (MH⁺); melting point: 128-131° C.

4-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)morpholine 110. HPLCpurity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.51 (d, J=2 Hz, 1H), 8.29(dd, J₁=2 Hz, J₂=8 Hz, 1H), 8.00 (d, J=2 Hz, 1H), 7.82 (d, J=8 Hz, 1H),7.74 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H), 3.67 (m, 4H),3.28 (m, 4H); melting point: 182-186° C.

4-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)morpholine 111. HPLCpurity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.59 (d, J=2 Hz, 1H), 8.44(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.65 (d, J=8 Hz, 1H),7.50 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 3.673 (m, 4H),3.26 (m, 4H); melting point: 168-170° C.

4-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)morpholine 112. HPLCpurity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.50 (d, J=2 Hz, 1H), 8.27(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J=8 Hz, 1H), 7.36 (d,J=7 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 3.67 (m, 4H), 3.28 (m, 4H), 2.33 (s,3H), 2.25 (s, 3H); melting point: 141-143° C.

4-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)morpholine 113. HPLCpurity: 100%; ¹H NMR (500 MHz. DMSO-d₆): δ 8.59 (d, J=2 Hz, 1H), 8.41(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.11 (d, J=7 Hz, 1H),7.05 (s, 1H), 6.85 (d, J=8 Hz, 1H), 3.64 (m, 4H), 3.27 (m, 4H), 2.31 (s,3H), 2.10 (s, 3H); melting point: 124-127° C.

4-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)thiomorpholine 114.HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.55 (d, J=2 Hz, 1H),8.27 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.98 (d, J=2 Hz, 1H), 7.80 (d, J=8 Hz,1H), 7.73 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 3.59 (m,4H), 2.70 (m, 4H); melting point: 189-191° C.

4-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)thiomorpholine 115.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.60 (d, J=2 Hz, 1H),8.42 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 7.66 (d, J=2 Hz,1H), 7.51 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 3.54 (m,4H), 2.67 (m, 4H); melting point: 191-194° C.

4-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)thiomorpholine 116.HPLC purity: 99.5%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.59 (d, J=2 Hz, 1H),8.40 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.12 (d, J=7 Hz,1H), 7.04 (s, 1H), 6.83 (d, J=8 Hz, 1H), 3.54 (m, 4H), 2.67 (m, 4H),2.32 (s, 3H), 2.09 (s, 3H); melting point: 130-137° C.

4-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)thiomorpholine 117.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.53 (d, J=2 Hz, 1H),8.25 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=7 Hz, 1H),7.36 (d, J=7 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 3.59 (m, 4H), 2.71 (m, 4H),2.33 (s, 3H), 2.24 (s, 3H); melting point: 144-147° C.

1-Cyclohexyl-4-(2-(2,5-dichlorophenylthio)-5-nitrophenylsulfonyl)piperazine118. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.50 (d, J=2 Hz,1H), 8.27 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.93 (d, J=2 Hz, 1H), 7.80 (d, J=8Hz, 1H), 7.72 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H), 3.26 (m,4H), 2.56 (m, 4H), 2.25 (m, 1H), 1.68 (m, 4H), 1.53 (m, 1H), 1.13 (m,4H), 1.02 (m, 1H); melting point: 153-155° C.

1-Cyclohexyl-4-(2-(2,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine119. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.49 (d, J=2 Hz,1H), 8.25 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.45 (s, 1H), 7.41 (d, J=7 Hz,1H), 7.35 (d, J=7 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 3.25 (m, 4H), 2.57 (m,4H), 2.32 (s, 3H), 2.26 (m, 1H), 2.25 (s, 3H), 1.69 (m, 4H), 1.54 (m,1H), 1.16 (m, 4H), 1.05 (m, 1H); melting point: 170-172° C.

1-Cyclohexyl-4-(2-(2,5-dimethylphenylthio)-5-nitrophenylsulfonyl)piperazine120. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.57 (d, J=2 Hz,1H), 8.43 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.56 (d, J=2Hz, 1H), 7.48 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 3.22 (m,4H), 2.52 (m, 4H), 2.23 (m, 1H), 1.69 (m, 4H), 1.54 (m, 1H), 1.14 (m,4H), 1.04 (m, 1H); melting point: 161-163° C.

1-Cyclohexyl-4-(2-(2,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine121. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.57 (d, J=2 Hz,1H), 8.40 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.10 (d, J=8Hz, 1H), 6.99 (s, 1H), 6.85 (d, J=8 Hz, 1H), 3.23 (m, 4H), 2.52 (m, 4H),2.30 (s, 3H), 2.26 (m, 1H), 2.09 (s, 3H), 1.68 (m, 4H), 1.54 (m, 1H),1.13 (m, 4H), 1.03 (m, 1H); melting point: 140-142° C.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)piperazine 122. HPLCpurity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.49 (d, J=2 Hz, 1H), 8.25(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J=8 Hz, 1H), 7.35 (d,J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 3.18 (m, 4H), 2.76 (m, 4H), 2.33 (s,3H), 2.24 (s, 3H); melting point: 142-145° C.

1-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)piperazine 123. HPLCpurity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.49 (d, J=2 Hz, 1H), 8.27(dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.96 (d, J=2 Hz, 1H), 7.81 (d, J=8 Hz, 1H),7.74 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 3.18 (m, 4H),2.74 (m, 4H); melting point: 150-153° C.

4-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)piperazin-2-one 124.HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.57 (d, J=2 Hz, 1H),8.29 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J=2 Hz, 1H),7.81 (d, J=8 Hz, 1H), 7.73 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.03 (d, J=8 Hz,1H), 3.89 (s, 2H), 3.59 (m, 2H), 3.24 (m, 2H); melting point: 252-255°C.

4-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)piperazin-2-one 125.HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.56 (d, J=2 Hz, 1H),8.27 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 8.17 (s, 1H), 7.45 (s, 1H), 7.42 (d,J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 3.90 (s, 2H),3.59 (m, 2H), 3.23 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H); melting point:196-202° C.

4-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)piperazin-2-one 126.HPLC purity: 99%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.63 (d, J=2 Hz, 1H),8.43 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 8.15 (s, 1H), 7.77 (d, J=8 Hz, 1H),7.68 (d, J=2 Hz, 1H), 7.52 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.08 (d, J=8 Hz,1H), 3.84 (s, 2H), 3.56 (m, 2H), 3.19 (m, 2H); melting point: 249-251°C.

1-(2-(2,5-Dichlorophenylthio)-5-nitrophenyl sulfonyl)-1,4-diazepane 127.HPLC purity: 99.5%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.56 (d, J=2 Hz, 1H),8.24 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.92 (d, J=2 Hz, 1H), 7.78 (d, J=8 Hz,1H), 7.71 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 3.50 (m,2H), 3.43 (m, 2H), 2.81 (m, 5H), 1.73 (m, 2H); melting point: 190-193°C.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)-1,4-diazepane 128.HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.55 (d, J=2 Hz, 1H),8.22 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J=8 Hz, 1H),7.34 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 3.50 (m, 2H), 3.48 (m, 2H),2.83 (m, 4H), 2.32 (s, 3H), 2.21 (s, 3H), 1.75 (s, 2H); melting point:80-90° C.

1-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)-4-(pyrrolidin-1-yl)piperidine129. HPLC purity: 100%; ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=3 Hz, 1H),8.10 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.72 (d, J=3 Hz, 1H), 7.54 (d, J=9 Hz,1H), 7.48 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 6.86 (d, J=9 Hz, 1H), 3.86 (m,2H), 3.00 (m, 2H), 2.54 (s, 4H), 2.18 (m, 1H), 1.96 (m, 2H), 1.78 (s,4H), 1.68 (m, 2H); MS (ESI, EI⁺): m/z=516 (MH⁺); melting point: 184-188°C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)-4-(pyrrolidin-1-yl)piperidine130. HPLC purity: 100%; ¹H NMR (500 MHz, CDCl₃) δ 8.87 (d, J=3 Hz, 1H),8.22 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.05 (d, J=7 Hz,1H), 6.85 (s, 1H), 6.70 (d, J=10 Hz, 1H), 3.87 (m, 2H), 2.99 (m, 2H),2.53 (m, 4H), 2.34 (s, 3H), 2.15 (s, 3H), 1.93 (m, 2H), 1.77 (m, 4H),1.65 (m, 3H); MS (ESI, EI⁺): m/z=460 (MH⁺); melting point: 95-102° C.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)-4-isopropylpiperazine131. HPLC purity: 99.6%; ¹H NMR (500 MHz, CDCl₃) δ 8.73 (d, J=2 Hz, 1H),8.02 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J=8 Hz, 1H),7.27 (d, J=6 Hz, 1H), 6.76 (d, J=9 Hz, 1H), 3.40 (t, J=4 Hz, 4H), 2.74(quintuplet, J=7 Hz, 1H), 2.64 (t, J=5.4H), 2.35 (s, 3H), 2.30 (s, 3H),1.04 (d, J=7 Hz, 6H); MS (ESI, EI⁺): m/z=450 (MH⁺); melting point:120-124° C.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)-4-methylpiperazine132. HPLC purity: 100%; ¹H NMR (500 MHz, CDCl₃) δ 8.75 (d, J=2 Hz, 1H),8.03 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J=8 Hz, 1H),7.27 (d, J=1 Hz, 1H), 6.77 (d, J=9 Hz, 1H), 3.43 (t, J=4 Hz, 4H), 2.53(t, J=5 Hz, 4H), 2.36 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H); MS (ESI,EI⁺): m/z=422 (MH⁺); melting point: 136-144° C.

1-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)-4-methylpiperazine133. HPLC purity: 100%; ¹H NMR (500 MHz, CDCl₃) δ 8.76 (d, J=2 Hz, 1H),8.11 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.71 (d, J=2 Hz, 1H), 7.55 (d, J=9 Hz,1H), 7.48 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 6.86 (d, J=9 Hz, 1H), 3.42 (m,4H), 2.51 (m, 4H), 2.31 (s, 3H); MS (ESI, EI⁺): m/z=461 (MH⁺); meltingpoint: 105-115° C.

1-(2-(2,5-Dichlorophenylthio)-5-nitrophenylsulfonyl)-4-methyl-1,4-diazepane134. HPLC purity: 100%; ¹H NMR (500 MHz, CDCl₃) δ 8.82 (d, J=3 Hz, 1H),8.10 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.71 (d, J=2 Hz, 1H), 7.53 (d, J=9 Hz,1H), 7.47 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 6.88 (d, J=9 Hz, 1H), 3.66 (m,2H), 3.57 (t, J=6 Hz, 2H), 2.72 (m, 4H), 2.39 (s, 3H), 1.96 (quintuplet,J=6 Hz, 2H); MS (ESI, EI⁺): m/z=476 (MH⁺); melting point: 116-119° C.

1-(2-(2,5-Dichlorophenoxy)-5-nitrophenylsulfonyl)-4-methylpiperazine135. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 8.59 (d, J=3 Hz,1H), 8.43 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.59 (d, J=2Hz, 1H), 7.50 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 3.26 (t.J=5 Hz, 4H), 2.35 (t, J=5 Hz, 4H), 2.16 (s, 3H); MS (ESI, EI⁺): m/z=446(MH⁺); melting point: 172-176° C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)-4-methyl-1,4-diazepane,hydrochloride 136. HPLC purity: 96.4%; ¹H NMR (500 MHz, CDCl₃) δ 12.50(s, 1H), 8.86 (d, J=3 Hz, 1H), 8.28 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.22 (d,J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.86 (s, 1H), 6.73 (d, J=9 Hz, 1H),4.12 (m, 1H), 3.84 (m, 2H), 3.52 (m, 2H), 3.40 (m, 1H), 3.32 (m, 1H),3.16 (m, 1H), 2.92 (m, 1H), 2.88 (d, J=5 Hz, 3H), 2.36 (s, 3H), 2.24 (m,1H), 2.11 (s, 3H); MS (ESI, EI⁺): m/z=420 (MH⁺): melting point: 268-275°C.

1-(2-(2,5-Dimethylphenylthio)-5-nitrophenylsulfonyl)-4-methyl-1,4-diazepane,hydrochloride 137. HPLC purity: 95.5%; ¹H NMR (500 MHz, DMSO-d₆): δ12.50 (s, 1H), 8.80 (d, J=2 Hz, 1H), 8.07 (dd, J₁=9 Hz, J₂=2 Hz, 1H),7.36 (s, 1H), 7.29 (m, 2H), 6.81 (d, J=9 Hz, 1H), 4.27 (d, J=17 Hz, 1H),3.98 (dd, J₁=16 Hz, J₂=11 Hz, 1H), 3.81 (m, 1H), 3.60 (d, J=13 Hz, 1H),3.48 (m, 1H), 3.43 (m, 1H), 3.37 (m, 1H), 3.22 (m, 1H), 2.93 (m, 1H),2.91 (d, J=5 Hz, 3H), 2.37 (s, 3H), 2.27 (s, 3H), 2.24 (m, 1H); MS (ESI,EI⁺): m/z=436 (MH⁺); melting point: 247-261° C.

Methyl4-(2-(2,5-dichlorophenylthio)-5-nitrophenylsulfonyl)piperazine-2-carboxylate139. HPLC purity: 97.5%; ¹H NMR (500 MHz, CDCl₃) δ 8.79 (d, J=2, 1H),8.13 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.72 (d, J=2 Hz, 1H), 7.55 (d, J=9 Hz,1H), 7.49 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 6.86 (d, J=9 Hz, 1H), 3.95 (dd,J₁=12 Hz, J₂=2 Hz, 1H), 3.72 (s, 3H), 3.64 (m, 2H), 3.17 (m, 3H), 2.95(m, 1H): MS (ESI, EI⁺): m/z=506 (MH⁺); melting point: 157-159° C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)-4-methylpiperazine,hydrochloride 146. HPLC purity: 98.5%; ¹H NMR (500 MHz, CDCl₃) δ 13.50(s, 1H), 8.84 (d, J=3 Hz, 1H), 8.28 (dd, J₁=9 Hz, J₂=3 Hz, 1H), 7.21 (d,J=8 Hz, 1H), 7.10 (s, 1H), 7.07 (d, J=8 Hz, 1H), 6.74 (d, J=9 Hz, 1H),4.06 (m, 2H), 3.86 (m, 2H), 3.48 (m, 2H), 2.83 (s, 3H), 2.38 (s, 3H),2.13 (s, 3H); MS (ESI, EI⁺): m/z=406 (MH⁺); melting point: 296-305° C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine,hydrochloride 148. HPLC purity: 100%; ¹H NMR (500 MHz, DMSO-d₆): δ 9.01(s, 1H), 8.60 (d, J=2 Hz, 1H), 8.43 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.33 (d,J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 7.02 (s, 1H), 6.85 (d, J=8 Hz, 1H),3.52 (m, 4H), 3.20 (m, 4H), 2.31 (s, 3H), 2.09 (s, 3H); melting point:80-84° C.

1-(2-(2,5-Dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine,dihydrochloride 148. HPLC purity: 98.4%; ¹H NMR (500 MHz, DMSO-d₆): δ9.45 (s, 2H), 8.60 (d, J=2 Hz, 1H), 8.43 (dd, J₁=2 Hz, J₂=8 Hz, 1H),7.33 (d, J=8 Hz, 1H), 7.13 (d, J=9 Hz, 2H), 6.84 (d, J=8 Hz, 1H), 3.58(m, 4H), 3.18 (m, 4H), 2.32 (s, 3H), 2.09 (s, 3H); MS (ESI, EI⁺):m/z=392 (MH⁺); melting point: 165° C.

Example 7 CCR3 Receptor Binding Assay

Cells were washed once with PBS and resuspended in a binding buffer (25mM HEPES pH 7.6, 5 mM MgCl₂, 1 mM CaCl₂, 0.5% BSA, 0.1% NaN₃), 100 mL ofcell suspension (2×10⁵ cells/well) and 0.1 nM [¹²⁵I]-labeled humaneotaxin/CCL11 (2000 Ci/mmol specific activity) were mixed in a 96-wellU-bottom polypropylene plate, and incubated for 60 min at roomtemperature for the binding reaction. The cell suspension was thentransferred to a filtration plate (#MAFB, Millipore), and washed 3 timeswith the binding buffer containing 0.5 M NaCl, scintillant added, andthe radioactivity was counted on a TopCount (Packard). For thedetermination of non-specific binding, the cell suspension and[¹²⁵I]-labeled human eotaxin/CCL11 were incubated in the presence of 500nM of unlabeled human eotaxin/CCL11. See, lino et al., “Molecularcloning and functional characterization of cynomolgus monkey (Macacafascicularis) CC chemokine receptor, CCR3,” Cytokine 2002, 19, 276-286.

The biological results are summarized in Tables 1 and 2, wherein Arepresents a value no greater than 10 nM; B represents a value greaterthan 10 nM but no greater than 25 nM; C represents a value greater than25 nM but no greater than 100 nM; D represents a value greater than 100nM but no greater than 500 nM; and E represents a value greater than 5nM.

TABLE 1 K_(i) K_(i) Cmpd # Free HCl^(a) Cmpd # Free HCl^(a) 51 D C 52 53C 54 D C 55 E 56 C C 57 E 58 E 59 E E 60 E E 61 B 62 E 63 E E 64 E E 65E 66 A 67 C D 68 C C 69 C D 70 D 71 E 72 E C 73 C 74 B A 75 A 76 A A 77A A 78 C C 79 A A 80 A A 81 A B 82 D 83 C A 84 A A 85 E 86 E 87 E 88 A89 B 90 B 91 B 92 C 93 E 94 95 D 96 C 97 D 98 C 99 B 100 A 101 E 102 E103 E 104 B 105 E 106 E 107 A 108 A 109 E 110 E 111 E 112 E 113 E 114 E115 E 116 E 117 E 118 B 119 A 120 E 121 A 122 D 123 B 124 A 125 E 126 B127 E 133 E 140 E 141 E 142 E 143 E 147 E C 148 E ^(a)HCl: Ahydrochloric acid salt of the corresponding compound.

TABLE 2 K_(i) Cmpd # Free HCl H₂SO₄ MeSO₃H EtSO₃H HNO₃ (CO₂H)₂ 80 A A AA A C C

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A method for the treatment, or amelioration ofone or more symptoms of asthma, allergic asthma, exercise inducedasthma, allergic rhinitis, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, conjunctivitis, allergicconjunctivitis, eosinophilic bronchitis, eosinophilic gastroenteritis,allograft rejection, chronic obstructive pulmonary disease, COPD(chronic obstructive pulmonary disorder), arthritis, rheumatoidarthritis, psoriatic arthritis, or osteoarthritis in a subject, whichcomprises administering to the subject a compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt or prodrug thereof;wherein: R¹ and R² are each independently (a) halo, cyano, nitro,hydroxyl, or guanidine; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio,wherein the alkyl, alkoxy, and alkylthio are each independently andoptionally substituted with one, two, or three halo; (c) C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, benzyl, phenoxy, benzoxy, or heterocyclyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);R³ is (a) hydrogen, halo, cyano, nitro, or hydroxyl; (b) C₁₋₆ alkyl,C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, and alkylthioare each independently and optionally substituted with one, two, orthree halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, or tetrazolyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);R⁴ is

R⁵ is (a) halo, cyano, nitro, hydroxyl, oxo, or guanidine; (b) C₁₋₆alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, andalkylthio are each independently and optionally substituted with one,two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, benzyl,phenoxy, benzoxy, or heterocyclyl; or (d) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or—S(O)₂NR^(1b)R^(1c); X is O or S; Y is —O—, —S—, —S(O)—, —S(O)₂—,—N(R^(1a))—, —C(R^(1a))(R^(1d))—, or —C(R^(1a))(NR^(1b)R^(1c))—; m is aninteger from 0 to 3; n is an integer from 1 to 3; p is an integer from 0to 4; r is an integer from 1 to 6; and each R^(1a), R^(1b), R^(1c), andR^(1d) is independently (a) hydrogen, phenyl, or benzyl; (b) C₃₋₇cycloalkyl, heteroaryl, or heterocyclyl, each optionally substituted; or(c) C₁₋₆ alkyl, optionally substituted with one, two, or threesubstituents, each independently selected from halo, hydroxyl, carboxy,alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; or each pair of R^(1b) and R^(1c) together withthe N atom to which they are attached independently form heteroaryl orheterocyclyl; with the proviso that when X is O; Y is —N(R^(1a))—; m andn are 1; R¹ and R² are each independently chloro, nitro, methyl, orisopropyl; R³ is nitro; and p is 0; then R^(1a) is not hydrogen.
 2. Themethod of claim 1, wherein the compound has the structure of Formula II:


3. The method of claim 1, wherein R⁵ is oxo; C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo; or —C(O)OR^(1a).
 4. The methodof claim 3, wherein R⁵ is oxo, methyl, or methoxycarbonyl.
 5. The methodof claim 1, wherein p is 0, 1, or
 2. 6. The method of claim 1, wherein mis
 1. 7. The method of claim 1, wherein n is 1 or
 2. 8. The method ofclaim 1, wherein Y is —O—, —S—, —S(O)—, or —S(O)₂—.
 9. The method ofclaim 1, wherein Y is —NR^(1a)—.
 10. The method of claim 9, whereinR^(1a) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, heteroaryl, orheterocyclyl.
 11. The method of claim 9, wherein R^(1a) is hydrogen,methyl, ethyl, propyl, pentyl, cyclopentyl, cyclohexyl, or3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl.
 12. The method of claim 1,wherein Y is —C(R^(1a))(R^(1d))—.
 13. The method of claim 12, whereinR^(1a) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, heteroaryl, orheterocyclyl.
 14. The method of claim 12, wherein R^(1a) is hydrogen,methyl, ethyl, propyl, pentyl, cyclopentyl, cyclohexyl, or3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl.
 15. The method of claim 12,wherein R^(1d) is hydrogen.
 16. The method of claim 1, wherein thecompound has the structure of Formula III:


17. The method of claim 16, wherein R^(1a) is hydrogen or C₁₋₆ alkyl.18. The method of claim 16, wherein R^(1b) is hydrogen or C₁₋₆ alkyl.19. The method compound of claim 16, wherein R^(1b) is ethyl.
 20. Themethod of claim 16, wherein R^(1c) is hydrogen or C₁₋₆ alkyl.
 21. Themethod of claim 16, wherein R^(1c) is ethyl.
 22. The method of claim 16,wherein R^(1b) and R^(1c) together with the N atom to which they areattached form heteroaryl or heterocyclyl.
 23. The method of claim 22,wherein R^(1b) and R^(1c) together with the N atom to which they areattached form 5- to 7-membered heterocyclyl.
 24. The method of claim 23,wherein the heterocyclyl is pyrrolidinyl or piperidinyl.
 25. The methodof claim 1, wherein R¹ is halo or C₁₋₆ alkyl.
 26. The method of claim25, wherein R¹ is fluoro, chloro, or methyl.
 27. The method of claim 1,wherein R² is halo or C₁₋₆ alkyl.
 28. The method of claim 27, wherein R²is fluoro, chloro, or methyl.
 29. The method of claim 1, wherein R¹ andR² are fluoro.
 30. The method of claim 1, wherein R¹ and R² are chloro.31. The method of claim 1, wherein R¹ and R² are methyl.
 32. The methodof claim 1, wherein R³ is cyano or nitro.
 33. The method of claim 1,wherein X is O.
 34. The method of claim 1, wherein X is S.
 35. Themethod of claim 1, wherein the compound is selected from the groupconsisting of:

and enantiomers, mixtures of enantiomers, mixtures of two or morediastereomers, tautomers, and mixtures of two or more tautomers thereof;and pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof.
 36. The method of claim 1, wherein the compound is ahydrochloride salt.
 37. The method of claim 1, wherein the disorder,disease, or condition is asthma, exercise induced asthma, allergicrhinitis, atopic dermatitis, chronic obstructive pulmonary disease, orallergic conjunctivitis.
 38. The method of claim 1, wherein the compoundis administered orally, parenterally, or topically.
 39. The method ofclaim 1, wherein the compound is administered in combination with asecond therapeutic agent.
 40. A method for modulating CCR3 activity,comprising contacting a CCR3 receptor with a compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt or prodrug thereof;wherein: R¹ and R² are each independently (a) halo, cyano, nitro,hydroxyl, or guanidine; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio,wherein the alkyl, alkoxy, and alkylthio are each independently andoptionally substituted with one, two, or three halo; (c) C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, benzyl, phenoxy, benzoxy, or heterocyclyl; or (d)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R³ is (a) hydrogen, halo,cyano, nitro, or hydroxyl; (b) C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₁₋₆alkylthio, wherein the alkyl, alkoxy, and alkylthio are eachindependently and optionally substituted with one, two, or three halo;(c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, or tetrazolyl; or (d) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);R⁴ is

R⁵ is (a) halo, cyano, nitro, hydroxyl, oxo, or guanidine; (b) C₁₋₆alkyl, C₁₋₆ alkoxy, or C₁₋₆ alkylthio, wherein the alkyl, alkoxy, andalkylthio are each independently and optionally substituted with one,two, or three halo; (c) C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, benzyl,phenoxy, benzoxy, or heterocyclyl; or (d) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or—S(O)₂NR^(1b)R^(1c); X is O or S; Y is —O—, —S—, —S(O)—, —S(O)₂—,—N(R^(1a))—, —C(R^(1a))(R^(1d))—, or —C(R^(1a))(NR^(1b)R^(1c))—; m is aninteger from 0 to 3; n is an integer from 1 to 3; p is an integer from 0to 4; r is an integer from 1 to 6; and each R^(1a), R^(1b), R^(1c), andR^(1d) is independently (a) hydrogen, phenyl, or benzyl; (b) C₃₋₇cycloalkyl, heteroaryl, or heterocyclyl, each optionally substituted; or(c) C₁₋₆ alkyl, optionally substituted with one, two, or threesubstituents, each independently selected from halo, hydroxyl, carboxy,alkoxy, carbamoyl, C₆₋₁₄ aryl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, C₃₋₇ cycloalkylcarbamoyl, and C₃₋₇heterocyclylcarbamoyl; or each pair of R^(1b) and R^(1c) together withthe N atom to which they are attached independently form heteroaryl orheterocyclyl; with the proviso that when X is O; Y is —N(R^(1a))—; m andn are 1; R¹ and R² are each independently chloro, nitro, methyl, orisopropyl; R³ is nitro; and p is 0; then R^(1a) is not hydrogen.